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[ CAS No. 923978-27-2 ] {[proInfo.proName]}

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Chemical Structure| 923978-27-2
Chemical Structure| 923978-27-2
Structure of 923978-27-2 * Storage: {[proInfo.prStorage]}
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Quality Control of [ 923978-27-2 ]

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Product Details of [ 923978-27-2 ]

CAS No. :923978-27-2 MDL No. :MFCD27987940
Formula : C22H24O4S Boiling Point : -
Linear Structure Formula :- InChI Key :AFLFKFHDSCQHOL-IZZDOVSWSA-N
M.W : 384.49 Pubchem ID :9864881
Synonyms :

Calculated chemistry of [ 923978-27-2 ]

Physicochemical Properties

Num. heavy atoms : 27
Num. arom. heavy atoms : 12
Fraction Csp3 : 0.27
Num. rotatable bonds : 7
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 110.62
TPSA : 88.9 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : No
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -5.03 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.29
Log Po/w (XLOGP3) : 5.09
Log Po/w (WLOGP) : 5.05
Log Po/w (MLOGP) : 3.68
Log Po/w (SILICOS-IT) : 5.46
Consensus Log Po/w : 4.51

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -5.3
Solubility : 0.00194 mg/ml ; 0.00000504 mol/l
Class : Moderately soluble
Log S (Ali) : -6.7
Solubility : 0.0000767 mg/ml ; 0.0000002 mol/l
Class : Poorly soluble
Log S (SILICOS-IT) : -6.1
Solubility : 0.000308 mg/ml ; 0.0000008 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 3.23

Safety of [ 923978-27-2 ]

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 [ 923978-27-2 ]

* 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.

  • Downstream synthetic route of [ 923978-27-2 ]

[ 923978-27-2 ] Synthesis Path-Downstream   1~30

YieldReaction ConditionsOperation in experiment
81%
  • 2
  • [ 2052-01-9 ]
  • [ 1778-09-2 ]
  • [ CAS Unavailable ]
  • [ 923978-27-2 ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; propan-1-ol at 50℃; for 2.33333h; 1 One pot synthesis of l-[(4-methylthio)phenyll-3-[(3,5-dimethyl-4- carboxydimethyloxy)phenyllprop-2-en-l-one (Elafibranor) performed as a multicomponent reaction 4-hydroxy-3,5-dimethylbenzaldehyde (300 mg; 2.0 mmol) was dissolved in THF (6 mL), pulverized NaOH (360 mg 9.0 mmol; 4.5 equiv.) was added and mixture was stirred until sodium phenolate was formed as a greenish yellow suspension. 1- propanol (2 mL) was added, suspension was heated to 50 °C and a solution of 2- bromo-2-methylpropanoic acid (1002 mg, 6.0 mmol; 3 equiv.) and 4- (methylthio)acetophenone (332 mg; 2.0 mmol; 1 equiv.) in THF (2 mL) was added over approximately 20 minutes. After the addition, the mixture was held at 50 °C for 2 h and solution of NaOH (400 mg; 10 mmol; 5.0 equiv.) in water (10 mL) was added. Reaction mixture was heated to reflux (66 - 67 °C), THF was distilled off and reaction was quenched by addition of 1M HCl to pH = 3.0-3.5. The mixture was taken up into MTBE and extracted with 1M Na2C03. The sodium salt of product, obtained by salting out after addition of appropriate amount of NaCl, was dissolved in water, acidified with 1M HCl to pH 2.0 and extracted with toluene. The product was obtained after concentration of toluenic solution under vacuum and crystallization as a yellow solid. Isolated yield: 61%, HPLC purity: 99.4%. (0094) 1H NMR (DMSO): δ 1.42 (s, 6H, C(CH3)2), 2.25 (s, 6Η, Ph-CHj), 2.57 (s, 3Η, S- CHs), 7.40 (m, 2Η, HAr), 7.56 (s, 2H, HAr), 7.64 (d, J = 15.5 Hz, 1H, CO-CH=CH- Ph), 7.82 (d, J = 15.7 Hz, 1H, CO-CH=CH-Ph), 8.1 1 (m, 2H, HAT), 12.95 (s, 1H, COOH). (0095) 13C NMR (DMSO): δ 13.94 (S-CHA 17.53 (2Ph-CHA 24.98 (CiCH^ 80.68 (O- C(CH3)2-COOH), 120.82 (CO-CH=CH-Ph), 124.90 (2CATH), 128.98 (2CATH), 129.30 (2CATH), 130.19 (CAT), 133.13 (2CAT), 133.89 (CAT), 143.31 (CO-CH=CH-Ph), 145.37 (CAT-S), 154.93 (CAT-O), 174.96 (COOH), 187.77 (C=0). (0096) HRMS (ESI+) m/z [C22H2504S]+ : calcd 385.1474; found 385.1470.
  • 3
  • [ 639784-17-1 ]
  • [ 923978-27-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: hydrogenchloride / ethanol 2: sodium hydroxide; water / methanol; tetrahydrofuran / 6 h / 20 °C
  • 4
  • [ 2172807-23-5 ]
  • [ 923978-27-2 ]
YieldReaction ConditionsOperation in experiment
4.3 g With water; sodium hydroxide In tetrahydrofuran; methanol at 20℃; for 6h; 5 Example- 5: (0090) Preparation of Elafibranor To a stirred solution of (£]-2-(2,6-dimethyl-4-(3-(4-(methylthio]phenyl]-3-oxoprop- l-en-l-yl]phenoxy]-2-methylpropanoate (5.0 g, 0.012 mol] in a mixture of methanol and tetrahydrofuran (2:1; 45 mL] was added sodium hydroxide (1.45 g, 0.036 mol] dissolved in water (5 mL] and stirring was continued for 6 hrs at ambient temperature. The organic solvent was removed under reduced pressure and the reaction mixture was diluted with water (50 mL] The reaction mixture was acidified and then extracted with dichloromethane (2 X 30 mL] Dichloromethane was removed under reduced pressure to give residue which was stirred in methanol (50 mL] The solid obtained was filtered and dried to give (£]- 2-(2, 6-dimethyl-4-(3-(4- (methylthio] phenyl]-3-oxoprop-l-en-l-yl] phenoxy]-2-methylpropanoic acid (4.3 g)·
  • 5
  • [ 923978-27-2 ]
  • [ 2377142-54-4 ]
YieldReaction ConditionsOperation in experiment
1.6 g With ammonium hydroxide In tetrahydrofuran at 20℃; for 22h; 8 Example-8: Preparation of ammonium salt of Elafibranor To a stirred solution of Elafibranor (2.0 g, 0.0051mol] in THF (20 mL], aq. ammonia solution (3.53 mL, 15 M] was added at ambient temperature. Reaction mixture was stirred for 22 Hrs at ambient temperature. Reaction mixture was concentrated and then triturated with isopropanol (20 mL] Solid obtained was filtered, washed with isopropanol and then dried to give 1.6 g of ammonium (E]-2-(2,6-dimethyl-4-(3-(4- (methylthio]phenyl]-3-oxoprop-l-en-l-yl]phenoxy]-2-methylpropanoate
  • 6
  • [ 923978-27-2 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
1.5 g With calcium acetate; sodium hydroxide In methanol; water at 20℃; for 2h; 11 Example- 11: Preparation of calcium salt of Elafibranor To a stirred solution of Elafibranor (2.0 g, 0.0051 mol] in methanol (15mL], sodium hydroxide solution (0.22 g in 5 mL water] was added followed by addition of calcium acetate (0.549 g, 0.0031 mmol] at ambient temperature and stirred for 2 Hrs. The reaction mass was cooled and filtered. Solid material was dried under vacuum to give 1.5 g of calcium salt of Elafibranor
  • 7
  • [ 923978-27-2 ]
  • [ CAS Unavailable ]
  • [ 2377142-55-5 ]
YieldReaction ConditionsOperation in experiment
2.1 g In tetrahydrofuran at 20℃; for 23h; 12 Example-12: Preparation of dimethyl ammonium salt of Elafibranor To a stirred solution of Elafibranor (2.0 g, 0.0051 mol] in tetrahydrofuran (20 mL], dimethylamine (5.2 mL, 2 M] was added at ambient temperature. Reaction mixture was stirred for 23 Hrs at ambient temperature. Reaction mixture was concentrated under reduced pressure to give 2.1 g of dimethyl ammonium salt of Elafibranor
  • 8
  • [ 923978-27-2 ]
  • [ CAS Unavailable ]
  • [ 2377142-56-6 ]
YieldReaction ConditionsOperation in experiment
2.3 g In tetrahydrofuran at 50℃; for 2h; 13 Example-13: Preparation of diethyl ammonium salt of Elafibranor To a stirred solution of Elafibranor (2.0 g, 0.0052 mol] in tetrahydrofuran (20 mL], diethyl amine (0.38 g, 0.0052 mol] was added at ambient temperature. Reaction mixture was stirred for 2 Hrs at 50 °C and then concentrated under reduced pressure to give 2.3 g of diethyl ammonium salt of Elafibranor
  • 9
  • [ 2233-18-3 ]
  • [ 923978-27-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: caesium carbonate / 48 h / 95 °C 2: hydrogenchloride / ethanol 3: sodium hydroxide; water / methanol; tetrahydrofuran / 6 h / 20 °C
Multi-step reaction with 3 steps 1: hydrogenchloride / ethanol 2: potassium carbonate / acetonitrile / 48 h / 85 °C 3: sodium hydroxide; water / methanol; tetrahydrofuran / 6 h / 20 °C
Multi-step reaction with 3 steps 1.1: hydrogenchloride / 1,4-dioxane / 30 h 2.1: caesium carbonate; tetra-(n-butyl)ammonium iodide / dimethyl sulfoxide; water / 0.5 h / 80 °C 2.2: 48 h / 80 °C 3.1: trifluoroacetic acid / dichloromethane / 3.5 h / 20 °C
Multi-step reaction with 3 steps 1: potassium carbonate / acetonitrile / 48 h / 80 °C 2: hydrogenchloride / isopropyl alcohol / 24 h / 20 °C 3: water; sodium hydroxide / N,N-dimethyl-formamide / 22 h / 20 °C
Multi-step reaction with 2 steps 1.1: hydrogenchloride / isopropyl alcohol / 24 h / 0 - 30 °C 2.1: acetone / 0.5 h / 0 - 5 °C 2.2: 20 - 25 °C
Multi-step reaction with 2 steps 1.1: hydrogenchloride / ethanol; water / 20 °C 2.1: sodium hydroxide / acetonitrile / 1 h / 70 °C 2.2: 2 h
Multi-step reaction with 3 steps 1: hydrogenchloride / ethanol; water / 20 °C 2: potassium carbonate / acetonitrile / 12 h / 80 °C 3: trifluoroacetic acid / dichloromethane / 12 h / 20 °C / Cooling with ice
Multi-step reaction with 3 steps 1: hydrogenchloride / methanol / 20 - 30 °C 2: potassium carbonate / acetonitrile / 20 h / 85 °C 3: trifluoroacetic acid / dichloromethane / 6 h / 25 °C

  • 10
  • [ 110-85-0 ]
  • [ 923978-27-2 ]
  • [ 2218534-96-2 ]
YieldReaction ConditionsOperation in experiment
1.7 g In tetrahydrofuran at 5 - 30℃; for 5h; 14 Example-14: Preparation of piperazine salt of Elafibranor To a stirred solution of Elafibranor (2.0 g, 0.0052 mol] in tetrahydrofuran (20 mL], Piperazine (0.44 g, 0.0052 mol] solution in THF (5 mL] was added at 5 °C. Reaction mixture was stirred for 5 Hrs at 30 °C and then filtered. Obtained solid was dried under reduced pressure to give 1.7 g of Piperazine salt of Elafibranor
  • 11
  • [ 110-85-0 ]
  • [ 923978-27-2 ]
  • [ 2218534-96-2 ]
YieldReaction ConditionsOperation in experiment
1.6 g In tetrahydrofuran at 5 - 55℃; for 5h; 15 Example-15: Preparation of piperazine bis-Elafibranor salt of Elafibranor To a stirred solution of Elafibranor (2.0 g, 0.0052 mol] in tetrahydrofuran (20 mL], Piperazine (0.228 g, 0.0026 mol] solution in tetrahydrofuran (5 mL] was added at 5 °C. Reaction mixture was stirred for 5 Hrs at 55 °C. Reaction mixture was cooled to ambient temperature and then filtered. Obtained solid was dried under reduced pressure to give 1.6 g of Piperazine bis Elafibranor salt
  • 12
  • [ 1778-09-2 ]
  • [ 923978-27-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: hydrogenchloride / ethanol 2: potassium carbonate / acetonitrile / 48 h / 85 °C 3: sodium hydroxide; water / methanol; tetrahydrofuran / 6 h / 20 °C
Multi-step reaction with 3 steps 1.1: hydrogenchloride / 1,4-dioxane / 30 h 2.1: caesium carbonate; tetra-(n-butyl)ammonium iodide / dimethyl sulfoxide; water / 0.5 h / 80 °C 2.2: 48 h / 80 °C 3.1: trifluoroacetic acid / dichloromethane / 3.5 h / 20 °C
Multi-step reaction with 2 steps 1.1: hydrogenchloride / isopropyl alcohol / 24 h / 0 - 30 °C 2.1: sodium hydroxide / 0.5 h / 0 - 5 °C 2.2: 20 - 25 °C
Multi-step reaction with 2 steps 1.1: hydrogenchloride / isopropyl alcohol / 24 h / 0 - 30 °C 2.1: acetone / 0.5 h / 0 - 5 °C 2.2: 20 - 25 °C
Multi-step reaction with 2 steps 1.1: hydrogenchloride / ethanol; water / 20 °C 2.1: sodium hydroxide / acetonitrile / 1 h / 70 °C 2.2: 2 h
Multi-step reaction with 3 steps 1: hydrogenchloride / ethanol; water / 20 °C 2: potassium carbonate / acetonitrile / 12 h / 80 °C 3: trifluoroacetic acid / dichloromethane / 12 h / 20 °C / Cooling with ice
Multi-step reaction with 3 steps 1: hydrogenchloride / methanol / 20 - 30 °C 2: potassium carbonate / acetonitrile / 20 h / 85 °C 3: trifluoroacetic acid / dichloromethane / 6 h / 25 °C

  • 13
  • [ 923978-99-8 ]
  • [ 923978-27-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate / acetonitrile / 48 h / 85 °C 2: sodium hydroxide; water / methanol; tetrahydrofuran / 6 h / 20 °C
Multi-step reaction with 2 steps 1.1: caesium carbonate; tetra-(n-butyl)ammonium iodide / dimethyl sulfoxide; water / 0.5 h / 80 °C 1.2: 48 h / 80 °C 2.1: trifluoroacetic acid / dichloromethane / 3.5 h / 20 °C
Multi-step reaction with 2 steps 1: potassium carbonate / acetonitrile / 20 h / 85 °C 2: trifluoroacetic acid / dichloromethane / 6 h / 25 °C
  • 14
  • [ 923978-25-0 ]
  • [ 923978-27-2 ]
YieldReaction ConditionsOperation in experiment
76.1% With trifluoroacetic acid In dichloromethane at 20℃; for 12h; Cooling with ice; 1 Comparative Example 1: Prepare GFT-505 with reference to US20060142611 method The compound II (3.0g) prepared by referring to the method in Example 1 was added to acetonitrile (20mL), potassium carbonate (2.1g) and tert-butyl 2-bromoisobutyrate (1.5g) were added successively, and the reaction The solution was reacted at 80°C for 12 hours; the inorganic salt was filtered out, potassium carbonate (2.1g) and tert-butyl 2-bromoisobutyrate (1.5g) were added, and then reacted at 80°C for 12 hours; the inorganic salt was filtered out again, and Potassium carbonate (2.1g) and tert-butyl 2-bromoisobutyrate (1.5g) were added for the third time, and reacted at 80°C for 12 hours. The reaction solution was filtered and concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain Intermediate III (2.7 g) as a yellow oil. The yield of this step was 61.3%. The obtained intermediate was dissolved in dichloromethane (9mL), and trifluoroacetic acid (4.5mL) was added dropwise under ice bath. The brown-red reaction solution was reacted at room temperature for 12 hours and then concentrated to dryness. Toluene was added and concentrated again. The residue was purified by column chromatography. (Dichloromethane: methanol = 20:1), to obtain 1.81 g of GFT-505, the yield of this step is 76.1%.
60% With trifluoroacetic acid In dichloromethane at 20℃; for 3.5h; 1.3 Step 3:
1-[4-methylthiophenyl]-(E)-3-[3,5-dimethyl-4-carboxydimethylmethyloxyhenyl]prop-2-en-1-one Step 3: 1-[4-methylthiophenyl]-(E)-3-[3,5-dimethyl-4-carboxydimethylmethyloxyhenyl]prop-2-en-1-one Intermediate 2 (25 g, 0.057 mol, 1 eq) is solubilised in 50 ml of dichloromethane, and 22 ml of trifluoroacetic acid (5 eq, 0.284 mol) is added gently. The reaction medium is stirred for 3.5 hours at ambient temperature and then the solvents are evaporated dry. Purification on silica gel (dichloromethane/methanol: 100/0→95/5); 13 g (yellow solid, yield 60%). Raw formula: C22H24O4S ESI-MS m/z=385.25 [M+H]+ 1H NMR DMSO-d6 δ ppm: 1.36 (s, 6H), 2.19 (s, 6H), 2.54 (s, 3H), 7.37 (d, J=8.6 Hz, 2H), 7.55 (s, 2H), 7.59 (d, J=15.6 Hz, 1 H), 7.80 (d, J=15.6 Hz, 1 H), 8.07 (d, J=8.6 Hz, 2H), 12.94 (s, 1H) The reaction diagram is given in FIG. 6. (0091) Results (0092) The analysis data of the 10.1 g of the batch obtained (EM0274L2) are summarised below: (0093) Molecular mass: 384.5 (exact mass: 384.1); (0094) 1H NMR spectrum: conforming to the structure, cf spectrum in FIG. 6A below. (0095) LCMS: TR=1.42 mn, m/z: 385.00=[M+H]+; (0096) Purity: >98% (1H NMR and LCMS); (0097) Melting point: 144-145° C. (0098) The appearance of the product is an amorphous yellow solid powder. The product exhibits significant absorption in the near visible with an apex at approximately 347 nm. (0099) The information is detailed in the following FIG. 7. (0100) The product obtained is conforming in terms of chemical purity and demonstrates absorption in the near visible that requires that the chemical stability under light and phototoxicity must therefore be checked.
86 % With trifluoroacetic acid In dichloromethane at 25℃; 4.1.3. General produce a for the preparation of compound 4s General procedure: To a solution of compound 3s (1.0 equiv.) in DCM, TFA (10.0 equiv.)was added. Subsequently, the reaction mixtures were stirred at 25 C,after 6 h, the reactions were completed. The solvents were removedunder reduced pressure to give residues, then the residues were dissolvedin DCM, and washed by NaHCO3, dried over MgSO4. The crudeproducts were purified with chromatography (petrol ether/EtOAc = 10/1) to give purified products.
  • 15
  • 2-[2,6-dimethyl-4-[(E)-3 -(4-methylsulfanylphenyl)-3-oxoprop-1-enyl]phenoxy]-2-methylpropanoic acid [ No CAS ]
  • [ 1115-70-4 ]
  • elafibranor metformin salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
The applicant prepared elafibranor metformin salt for the purpose of determining its characteristics and to compare them with elafibranor in free basic form, with the objective of producing pharmaceutical compositions. Experimental Protocol The batches of elafibranor metformin salts are produced from a batch of free basic elafibranor. 1 g of GFT505 (2.6 mmol) and 104 mg of NaOH (1 eq, 2.6 mmol) are put in suspension in 8 ml of isopropanol and 10 ml of methanol and heated to 65 C. A solution of 431 mg of metformin.Cl (1 eq, 2.6 mmol) in 2 ml of isopropanol is added to the yellow reaction medium and stirred for 30 minutes at 65 C. After returning to ambient temperature, the fine suspension is filtered quickly, washed by 2×1 ml of isopropanol. After approximately 30 minutes, a pale yellow solid begins to precipitate. After 24 hours at ambient temperature, the solid is filtered, washed with 2×1 ml of isopropanol and dried for 24 hours at 45 C. under vacuum. The yellow residue is resolubilised in 10 ml of isopropanol and 6 ml of methanol at 65 C. Heating is stopped and the clear reaction medium is left to cool under stirring. A solid begins to precipitate at around 47 C. After 24 hours, the solid is filtered, washed with 2×1 ml of isopropanol and dried for 72 hours at 45 C. under vacuum (batch CP0685L1, see Report No. 1 of 30 August 2016). After 10 days of additional drying at 45 C. under high vacuum (<10-2 mbar), the traces of solvent detected in the previous batch have disappeared (batch CP0685L2). The products are next stored cool (2-8 C.) under inert gas to prevent any degradation. An analysis of the product is carried out, including identification and chemical purity (see FIG. 8). Results: The results were as follows: Molecular mass: 513 Appearance: amorphous yellow solid. Melting point: 178/180 C. TR=1.46 mn, m/z: 385=[M+H]+ Other data illustrated in FIG. 8.
  • 16
  • [ 2412096-10-5 ]
  • [ 923978-27-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: water; sodium hydroxide / isopropyl alcohol / 12 h / 40 - 45 °C 2: di-tert-butyl peroxide / acetonitrile / 12 h / 90 °C
  • 17
  • [ 624-92-0 ]
  • [ CAS Unavailable ]
  • [ 923978-27-2 ]
YieldReaction ConditionsOperation in experiment
60% With di-tert-butyl peroxide In acetonitrile at 90℃; for 12h; 5; 12 Example 5: Synthesis of Elafibranor Compound of Formula IX (84.5 g, 0.22 M, 1.0 eq.), 1 ,2-dimethyldisulfide (41.4 g, 0.44 M, 2.0 eq.), di-tertiarybutyl peroxide (DTBP) (96.5 g, 0.66 M, 3.0 eq.), and MeCN (300 ml) were taken in a 5.0 L RBF. The reaction mixture was stirred at 90 °C for 12 h in air. After cooling to room temperature, the product was diluted with fFO (1.5 L) and extracted with EtOAc (4 x 1.0 L). The extracts were combined and washed by brine (3 x 1.0 L) and dried over Na2S04. The mixture was filtered, and filtrate was evaporated. Cmde material was dissolved in tetrahydrofuran (425 ml) and added hexane dropwise (675 ml). The mixture was cooled to 15-20 °C. Elafibranor crystallizes out and stirred for 2 hrs. Material was filtered, suck dried and finally vacuum oven dried at 45-50 °C for 12 hrs to get the compound of Formula II. Yield: 51 g, 60% Purity: 99.92% on HPLC
  • 18
  • [ 2412096-12-7 ]
  • [ 923978-27-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: magnesium; iodine / tetrahydrofuran / 2 h / Reflux 1.2: 2 h / 0 - 20 °C 2.1: Jones reagent / acetone / 6 h / 0 - 20 °C 3.1: tris(pentafluorophenyl)borate; triethylsilane / 8 h / 100 °C
Multi-step reaction with 3 steps 1.1: magnesium; iodine / tetrahydrofuran / 2 h / Reflux 1.2: 2 h / 0 - 20 °C 2.1: Jones reagent / acetone / 6 h / 0 - 20 °C 3.1: di-tert-butyl peroxide / acetonitrile / 12 h / 90 °C
  • 19
  • [ 2412096-13-8 ]
  • [ 923978-27-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: potassium carbonate / acetone / 0.25 h 1.2: 12 h / Reflux 2.1: magnesium; iodine / tetrahydrofuran / 2 h / Reflux 2.2: 2 h / 0 - 20 °C 3.1: Jones reagent / acetone / 6 h / 0 - 20 °C 4.1: di-tert-butyl peroxide / acetonitrile / 12 h / 90 °C
Multi-step reaction with 4 steps 1.1: potassium carbonate / acetone / 0.25 h 1.2: 12 h / Reflux 2.1: magnesium; iodine / tetrahydrofuran / 2 h / Reflux 2.2: 2 h / 0 - 20 °C 3.1: Jones reagent / acetone / 6 h / 0 - 20 °C 4.1: tris(pentafluorophenyl)borate; triethylsilane / 8 h / 100 °C
  • 20
  • [ 923978-51-2 ]
  • [ 923978-27-2 ]
YieldReaction ConditionsOperation in experiment
70% With triethylsilane; tris(pentafluorophenyl)borate at 100℃; for 8h; 9 Example 9: Synthesis of Elafibranor In a 4-neck, oven-dried 500 mL RBF was charged with tris-(pentsfluorophenyl)borane (2.32 g, 0.01 M, 10 mol%), Triethyl silane(l 16 g, 1.0 M, 10 equiv), and compound of Formula XV (41.6 g, 0.1 M, 1.0 eq.). The solution in RBF was air evacuated and heated to 100 °C for 8 h. The reaction mass was cooled to ambient temperature and passed through a small plug of silica gel using Et20 (250 ml). The ethereal solution was dried (Na2S04) and filtered, and the solvent was removed under reduced pressure. The mixture was then subjected to high vacuum at 70 °C until the unreacted hydrosilane was removed from the system. Cmde material was dissolved in tetrahydrofirran (200 ml) and added hexane dropwise (325 ml). The mixture was cooled to 15-20 °C. Elafibranor crystallizes out and stirred for 2 hrs. Material was filtered, suck dried and finally vacuum oven dried at 45-50 °C for 12 hrs to get compound of Formula II. Yield: 26.9 g, 70%. Purity: 99.85% on HPLC
  • 21
  • [ 2412096-15-0 ]
  • [ 923978-27-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: Jones reagent / acetone / 6 h / 0 - 20 °C 2: di-tert-butyl peroxide / acetonitrile / 12 h / 90 °C
  • 22
  • [ 2412096-16-1 ]
  • [ 923978-27-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: hydrogenchloride / isopropyl alcohol / 24 h / 20 °C 2: water; sodium hydroxide / N,N-dimethyl-formamide / 22 h / 20 °C
  • 23
  • [ 2412096-17-2 ]
  • [ 923978-27-2 ]
YieldReaction ConditionsOperation in experiment
89% With water; sodium hydroxide In N,N-dimethyl-formamide at 20℃; for 22h; 15 Example 15: Synthesis of Elafibranor To a compound of Formula XXI (84.9 g, 0.2 M, 1.0 eq.) in dimethyl formamide (5.0 mL) was added NaOH (0.236 g, 0.006 M, 5.0 eq) and DM Water (2.0 mL) and stirred for 22 hrs at Rroom temperature. After reaction completion, as monitored by TLC, was added DM Water (10 mL) and Ethyl Acetate (10 mL) and stirred for 30 min. pH was adjusted to 5 with cone HC1 and layer separated. The ethyl acetate layer was degassed. Yield Elafibranor of Formula II. Yield: (67.92g, 89%)
  • 24
  • [ 2412096-07-0 ]
  • [ 923978-27-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: Jones reagent / acetone / 6 h / 0 - 20 °C 2.1: aluminum (III) chloride; oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 2.2: 12 h / 20 °C 3.1: water; sodium hydroxide / isopropyl alcohol / 12 h / 40 - 45 °C 4.1: di-tert-butyl peroxide / acetonitrile / 12 h / 90 °C
  • 25
  • [ 2412096-08-1 ]
  • [ 923978-27-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: potassium carbonate / acetone / 0.25 h 1.2: 12 h / Reflux 2.1: Jones reagent / acetone / 6 h / 0 - 20 °C 3.1: aluminum (III) chloride; oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 3.2: 12 h / 20 °C 4.1: water; sodium hydroxide / isopropyl alcohol / 12 h / 40 - 45 °C 5.1: di-tert-butyl peroxide / acetonitrile / 12 h / 90 °C
  • 26
  • [ 2412096-09-2 ]
  • [ 923978-27-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: aluminum (III) chloride; oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C 1.2: 12 h / 20 °C 2.1: water; sodium hydroxide / isopropyl alcohol / 12 h / 40 - 45 °C 3.1: di-tert-butyl peroxide / acetonitrile / 12 h / 90 °C
  • 27
  • [ 923978-99-8 ]
  • [ 67-66-3 ]
  • [ CAS Unavailable ]
  • [ 923978-27-2 ]
YieldReaction ConditionsOperation in experiment
55% Stage #1: (2E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-[4-(methylsulfanyl)phenyl]prop-2-en-1-one; acetone With sodium hydroxide at 0 - 5℃; for 0.5h; Stage #2: chloroform at 20 - 25℃; 2 Example 2: 2-(2,6-dimethyl-4-{(lE)-3-[4-(methylsulfanyl)phenyl]-3-oxoprop-l-en-l-yl}phenoxy)-2-methylpropanoic acid (Elafibranor, I) Pulverized sodium hydroxide (13.2g, 0.33mol) was added to a suspension of compound IV (lO.Og, 0.033mol) in acetone (lOOml). The reaction mixture was stirred at about 0°C to about 5°C for about 30min; chloroform (4.4g, 0.036mol) was added drop wise over the course of about 30min and stirred overnight at about 20°C to about 25°C. After completion of reaction, acetone was removed under vacuum. The residue was dissolved in water (lOOml), acidified with hydrochloric acid (HC1) and extracted with ethyl acetate. The organic layer was separated and concentrated under vacuum to obtain the crude product which was purified by column chromatography to furnish 2-(2,6- dimethyl-4- {( 1 E)-3 - [4-(methylsulfanyl)phenyl] -3 -oxoprop- 1 -en- 1 -yl} phenoxy)-2- methylpropanoic acid elafibranor (I) as a pale yellow solid of (7.0 g, 55% yield; purity>99%) ' H NMR CDCh d ppm: 1.55 (s, 6H), 2.29 (s, 6H), 2.55 (s, 3H), 7.31 (d, J= 8.55Hz, 2H), 7.44 (s, 2H), 7.73 (d, J= 15.5Hz, 1H), 7.97 (d, J= 8.55Hz, 2H), 12.97 (s, 1H) MS (ES-MS): 383.3 (M-l)
  • 28
  • [ 923978-99-8 ]
  • [ 57-15-8 ]
  • [ 923978-27-2 ]
YieldReaction ConditionsOperation in experiment
59% Stage #1: (2E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-[4-(methylsulfanyl)phenyl]prop-2-en-1-one; 1,1,1-trichloro-2-methyl-2-propanol In acetone at 0 - 5℃; for 0.5h; Stage #2: With sodium hydroxide In acetone at 20 - 25℃; 3; 4; 5 Example 4: Preparation of 2-(2,6-dimethyl-4-{(lE)-3-[4-(methylsulfanyl)phenyl]-3- oxoprop-l-en-l-yl}phenoxy)-2-methylpropanoic acid (Elafibranor, I) l,l,l-trichloro-2-methylpropan-2-ol (8.8g, 0.05mol) was added to a suspension of compound IV (10. Og, 0.033mol) in acetone (lOOml). The reaction mixture was stirred at about 0°C to about 5°C for about 30min and pulverized sodium hydroxide (6.6g, 0. l65mol) was added in lots over the course of about 3h. The reaction mixture was stirred overnight at about 20°C to about 25°C. After completion of the reaction, acetone was removed under vacuum to afford a residue which was dissolved in water; acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was separated and concentrated under vacuum to yield crude oil. The crude oil was dissolved in ethyl acetate, benzyl amine (3.94 g, 0.036mmol) was added to it, refluxed for about lh and stirred overnight. The solid obtained was filtered, washed with ethyl acetate and dried in air oven. The dry solid was added in water, basified using aq sodium hydroxide under stirring. The reaction mass was washed with dichloromethane, distilled to remove traces of dichloromethane and acidified using dil. Hydrochloric acid under stirring. The solid was filtered, washed with water and dried in an air oven to obtain 2-(2,6-dimethyl-4-{(lE)-3-[4-(methylsulfanyl)phenyl]-3-oxoprop-l- en-l-yl}phenoxy)-2-methylpropanoic acid (elafibranor, I) as a pale yellow solid (7.6 g, 59% yield; purity >99.5%; Z-isomer less than 2% w/w) 1H NMR CDCh d ppm: 1.55 (s, 6H), 2.29 (s, 6H), 2.55 (s, 3H), 7.31 (d, J = 8.55Hz, 2H), 7.44 (s, 2H), 7.73 (d); , J = 15.5Hz, 1H), 7.97 (d, J = 8.55Hz, 2H), 12.97 (s, 1H).
  • 29
  • [ 923978-99-8 ]
  • [ 2052-01-9 ]
  • [ 923978-27-2 ]
YieldReaction ConditionsOperation in experiment
82.5% Stage #1: (2E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-[4-(methylsulfanyl)phenyl]prop-2-en-1-one With sodium hydroxide In acetonitrile at 70℃; for 1h; Stage #2: 2-bromo-2-methylpropionic acid In acetonitrile for 2h; 2-5; 5; 6; 6; 7; 7-8 Example 2: Preparation of GFT-505 Sodium hydroxide (20g, 0.5mol) and acetonitrile (100mL) were added to the reaction flask, and a solution of compound II (30g, 0.1mol) and acetonitrile (200mL) was added while stirring; the red reaction solution was incubated at 70°C for 1 hour. At the same temperature, 2-bromoisobutyric acid (25 g, 0.15 mol) in acetonitrile (150 mL) was dropped into the reaction solution, and the progress of the reaction was monitored by thin layer chromatography (TLC). After 2 hours of reaction, TLC showed that the reaction of Compound II was complete. The reaction solution was poured into 200 mL ice water, acidified with 6N hydrochloric acid (pH less than 3), and extracted with ethyl acetate (500 mL); the organic phase was washed with saturated brine, dried and concentrated, and the residue was recrystallized from acetonitrile to obtain GFT-505 31.7g, total yield 82.5%,
  • 30
  • [ 2052-01-9 ]
  • [ 1778-09-2 ]
  • [ 2233-18-3 ]
  • 2-(2,6-dimethyl-4-{(1E)-3-[4-(methylsulfanyl)phenyl]-3-oxoprop-1-en-1-yl}phenoxy)-2-methylpropanoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
45.5% Stage #1: 4-hydroxy-3,5-dimethylbenzaldehyde With sodium hydroxide In tetrahydrofuran Stage #2: 2-bromo-2-methylpropionic acid; 4-(Methylthio)acetophenone With sodium hydroxide In tetrahydrofuran; propan-1-ol at 50℃; for 2h; 2 Comparative Example 2: Prepare GFT-505 with reference to WO2019025017 method 3,5-Dimethyl-4-hydroxybenzaldehyde (300mg, 2mmol) was dissolved in tetrahydrofuran (6mL), sodium hydroxide (360mg, 9mmol) was added and stirred well until a yellow-green phenol sodium salt was formed. After adding n-propanol (2mL) to the suspension, the temperature was raised to 50°C; 2-bromoisobutyric acid (1002mg, 6mmol) and 4-methylthioacetophenone (332mg, 2mmol) were dissolved in 2mL of tetrahydrofuran. The mixed solution was slowly dropped into the above sodium salt suspension, and reacted at 50°C for 2 hours. 1M sodium hydroxide solution (10 mL) was added to the reaction solution, the reaction mixture was heated up and the tetrahydrofuran was evaporated; 1M hydrochloric acid was added to the residue. After the resulting mixture was extracted with methyl tert-butyl ether, it was washed with 1M sodium carbonate solution. Add appropriate amount of sodium chloride to the mixed solution to ensure that the final product sodium salt precipitates. The collected sodium salt was acidified again with 1M hydrochloric acid and extracted with toluene. After the extract was concentrated and crystallized, 350 mg of GFT-505 was obtained, with a yield of 45.5%.
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