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Chemical Structure| 156897-06-2
Chemical Structure| 156897-06-2
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Product Details of [ 156897-06-2 ]

CAS No. :156897-06-2 MDL No. :MFCD00929900
Formula : C23H22ClNO2 Boiling Point : -
Linear Structure Formula :- InChI Key :UAWXGRJVZSAUSZ-UHFFFAOYSA-N
M.W : 379.88 Pubchem ID :133021
Synonyms :
ML-3000

Safety of [ 156897-06-2 ]

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

Application In Synthesis of [ 156897-06-2 ]

* 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 [ 156897-06-2 ]

[ 156897-06-2 ] Synthesis Path-Downstream   1~57

  • 1
  • [ 156897-35-7 ]
  • [ 156897-06-2 ]
YieldReaction ConditionsOperation in experiment
64% The mixture of the ester (IVa) (0.5 g, 1.2 mmol), ethanol (3 ml) and 10 % of NaOH (1 ml) was stirred under slight reflux for 30 minutes. Then the mixture was poured into diluted hydrochloric acid (10 ml) and extracted with ether (3x5 ml). The combined extracts were evaporated until dryness and the evaporation residue was re-crystallized from ethanol. The desired product (I) was obtained in the yield of 64%, melting temp. 164-166 0C-1H-NMR spectrum (CDCl3): 1.30s, 6H (2xCH3); 2.85s, 2H (CH2); 3.57s, 2H (CH2); 3.75s, 2H (CH2); 7.02-7.27m, 9HAr.
  • 2
  • 2,2,2-trichloroethyl 2,3,4-tri-O-tert-butyldimethylsilyl-D-glucopyranuronate [ No CAS ]
  • [ 156897-06-2 ]
  • (2S,3R,4S,5R)-3,4,5-Tris-(tert-butyl-dimethyl-silanyloxy)-6-{2-[2-(4-chloro-phenyl)-6,6-dimethyl-1-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl]-acetoxy}-tetrahydro-pyran-2-carboxylic acid 2,2,2-trichloro-ethyl ester [ No CAS ]
  • 3
  • [ 3355-31-5 ]
  • (1,2-dimethyl-3-zirconacyclopent-1-ene)(C5H5)2 [ No CAS ]
  • [ 156897-06-2 ]
  • 10
  • [ 3355-31-5 ]
  • [ 156897-06-2 ]
  • 14
  • [ 156897-06-2 ]
  • [ 530-62-1 ]
  • [ 1175530-60-5 ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; at 20℃; for 0.5h; 6-(4-Chlorphenyl)-2,3-dihydro-1-hydroxy-2,2-dimethyl-7-phenyl-1Hpyrrolizin-5-yl]-essigsaeure (ML3000, 10.0 g, 26.3 mmol), hergestellt nach Laufer et al. (J. Med. Chem. 1994, 37, 1894-1897) wird in 40 mL absolutem THF geloest und mit 5.1 g (31.5 mmol) Carbonyldiimidazol versetzt. Man ruehrt 30 min bis das Imidazolid bei Raumtemperatur ausfaellt, setzt dann 80 mL tert-Butanol zu und erhitzt am Wasserabscheider auf 100 C. Sobald das THF vollstaendig ueberdestilliert ist, erhitzt man die Reaktionsmischung weitere 7 Tage auf 110 C. Dann laesst man abkuehlen und ruehrt mit 80 mL Diethylether oder MeOH aus. Das Kristallisat wird durch Absaugen vom Loesungsmittel befreit und getrocknet. Aus der Mutterlauge laesst sich durch Einrotieren und Faellen mit MeOH weiteres Kristallisat gewinnen. Ausbeute: 8.0 g (70%), C27H30ClNO2 436.0 g/mol, Smp.: 168 C. IR (KBr): 1/lambda (cm-1) = 2954, 2870,1728 (CO Ester), 1487, 1379, 1163, 1151, 1097, 822, 700. - 1H-NMR (CDCl3): delta (ppm) = 7.27 - 7.03 (m, 9 H, 2 Ar.), 3.75 (s, 2 H, CH2), 3.41 (s, 2 H, CH2), 2.84 (s, 2 H, CH2), 1.47 (s, 9 H, (CCH3)3), 1.29 (s, 6 H, 2-CH3).13C-NMR (CDCl3): delta (ppm) = 170.1 (CO), 136.1, 134.8, 133.9, 131.5, 131.6, 128.2, 128.1, 128.0, 124.6, 118.4, 114.6 , 81.2 (OC(CH3)3), 58.3 (CH2), 43.3 (C-2), 40.5 (CH2), 32.9 (CH2), 28.1 (OC(CH3)3), 28.0 (C(CH3)2). CHN: ber. C 74.38, H 6.94, N 3.21, gef. C 73.99, H 6.90, N 3.21.
  • 15
  • [ 156897-06-2 ]
  • [2-(4-chlorophenyl)-6,6-dimethyl-1-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl]acetic acid 2-(4-chlorophenyl)-6,6-dimethyl-1-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl ester [ No CAS ]
  • 16
  • [ 108-88-3 ]
  • [ 156897-06-2 ]
  • 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-ylacetic acid toluene hemisolvate [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% In diethyl ether; at 60℃; 6- (4-Chlorophenyl) -2, 2-dimethyl-7-phenyl-2, 3-dihydro- lH-pyrrolizin-5-ylacetic acid (4 g) is dissolved under reflux (600C) in a solvent mixture composed of diethyl ether and toluene in the ratio 1:1 (40 ml) . A saturated solution with a pale yellow colour is obtained and is rapidly filtered while still hot under pressure and is then slowly cooled while stirring with a reflux condenser by immersion in an oil bath equilibrated at 350C and finally with the stirring switched off to room temperature over the course of 6 h. It is then stored in a refrigerator at 40C for 16 hours. The crystals are removed by filtration of the mother liquor through a G4 filter under a nitrogen pressure and adhering residues of mother liquor are removed by passing air through the bed of powder for 10 minutes. The toluene solvate is obtained in the form of fine white crystals in a yield of 70% and purity of 99.83%.
  • 17
  • [ 108-88-3 ]
  • [ 156897-06-2 ]
  • 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-ylacetic acid toluene solvate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In ethyl acetate; at 40 - 50℃; 30 1 of ethyl acetate are distilled out of a solution of crude 6- (4-chlorophenyl) -2, 2-dimethyl-7-phenyl-2, 3- dihydro-lH-pyrrolizin-5-ylacetic acid (12 kg) in ethyl acetate (125 1) at 40-500C under reduced pressure and are replaced by 30 1 of toluene. Subsequently, a further 30 1 of ethyl acetate are distilled out of the mixture in vacuo. The crystals which form during this are removed by centrifugation, washed with toluene (2 1), resuspended in toluene (11 1) and again centrifuged. After washing with toluene (1 1), the crystals (toluene solvate) from a number of batches are collected, suspended in ethyl acetate (45 1) under nitrogen and stirred at 0-50C for 2 hours, and subsequently centrifuged. The centrifugate is washed with ethyl acetate (2 x 8 1) and resuspended in methanol (60 1) at 0-50C for 3 hours, and finally centrifuged, and the centrifugate is washed with methanol (4 1) and the product is dried in vacuo at 20 mbar and 500C for 2 days. Polymorph B of 6- (4-chlorophenyl) -2 , 2-dimethy1-7-phenyl-2, 3-dihydro- lH-pyrrolizin-5-ylacetic acid is obtained in a purity of 99.69%.Solid state 13C-NMR spectrum and X-ray diffraction diagram are shown in Figures 2a and 2b, and 3, respectively.
  • 18
  • 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-ylacetic acid toluene solvate [ No CAS ]
  • [ 156897-06-2 ]
YieldReaction ConditionsOperation in experiment
In methanol; ethyl acetate; at 0 - 5℃; for 5h; 30 1 of ethyl acetate are distilled out of a solution of crude 6- (4-chlorophenyl) -2, 2-dimethyl-7-phenyl-2, 3- dihydro-lH-pyrrolizin-5-ylacetic acid (12 kg) in ethyl acetate (125 1) at 40-500C under reduced pressure and are replaced by 30 1 of toluene. Subsequently, a further 30 1 of ethyl acetate are distilled out of the mixture in vacuo. The crystals which form during this are removed by centrifugation, washed with toluene (2 1), resuspended in toluene (11 1) and again centrifuged. After washing with toluene (1 1), the crystals (toluene solvate) from a number of batches are collected, suspended in ethyl acetate (45 1) under nitrogen and stirred at 0-50C for 2 hours, and subsequently centrifuged. The centrifugate is washed with ethyl acetate (2 x 8 1) and resuspended in methanol (60 1) at 0-50C for 3 hours, and finally centrifuged, and the centrifugate is washed with methanol (4 1) and the product is dried in vacuo at 20 mbar and 500C for 2 days. Polymorph B of 6- (4-chlorophenyl) -2 , 2-dimethy1-7-phenyl-2, 3-dihydro- lH-pyrrolizin-5-ylacetic acid is obtained in a purity of 99.69%.Solid state 13C-NMR spectrum and X-ray diffraction diagram are shown in Figures 2a and 2b, and 3, respectively.
  • 19
  • [ 83905-01-5 ]
  • [ 156897-06-2 ]
  • C61H92ClN3O13 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dicyclohexyl-carbodiimide; In tetrahydrofuran; at 0 - 20℃; for 13h; Example 3: Compound 1; A stirred solution of 1.5 g of azithromycin in 9 ml of dry THF was cooled to 00C and EPO <DP n="25"/>1.1 g of <strong>[156897-06-2]licofelone</strong> was added, followed by 0.59 g of DCC. After 1 h the mixture was allowed to come to ambient temperature and was stirred for another 12 h. The mixture was filtered and the filtrate concentrated in vacuum. The residue was taken up in toluene and chromatographed on silica gel (column 15 cm x 2.5 cm, elution with chloroform:isopropanol:amrnonia (7 M in methanol) 40:1 :1 to yield the desired product.
  • 20
  • [ 156897-06-2 ]
  • roxithromycin [ No CAS ]
  • C64H96ClN3O16 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dicyclohexyl-carbodiimide; In tetrahydrofuran; at 0 - 20℃; for 16.5h; Example 5: Compound 3; A suspension of 1.2 g of roxithromycin in 6 ml of THF was cooled to 00C and 820 mg of <strong>[156897-06-2]licofelone</strong> was added under rapid stirring, followed by 430 mg of DCC. The mixture was kept at the same temperature for 30 min and was then allowed to come to ambient temperature. After another 16 h the mixture was filtered and the filtrate concentrated in vacuum. The residue was chromatographed on silica gel, elution with chloroform:isopropanol:ammonia (7 M in methanol) 25:1 :1 to yield the desired product, 1.5 g, as colorless solid.
  • 21
  • [ 156897-06-2 ]
  • [ 117693-41-1 ]
  • [ 922724-94-5 ]
YieldReaction ConditionsOperation in experiment
With dicyclohexyl-carbodiimide; In tetrahydrofuran; at 0 - 20℃; for 12.5h;Product distribution / selectivity; Example 7: Compound 2; 20 ml of dry THF were placed in a round bottom flask in which 5.9 g of M1 were suspended. The mixture was cooled to 0-50C in an ice bath and 5.2 g of <strong>[156897-06-2]licofelone</strong> were added, immediately followed by 2.8 g of DCC. The mixture was stirred for 0.5 h at the same temperature and then the ice bath was removed. The mixture was stirred for another 12 h at ambient temperature and then filtered. The residue was washed with 20 ml of dichloromethane. All volatiles were removed in vacuum. The residue was taken up in 5 ml of toluene and 5 ml of dichloromethane and transferred on a column of silica gel, 35 cm x 4.5 cm, packed as a slurry in EPO <DP n="28"/>dichloromethane:isopropanol:ammonia (7 M in methanol) 100:1 :1. As eluent 600 ml of dichloromethane:isopropanol:ammonia (7 M in methanol) 60:1 :1 , changing to dichloromethane:isopropanol:ammonia (7 M in methanol) 30:1 :1 were used. The collected fractions containing the product were evaporated at reduced pressure with a bath temperature not exceeding 30C to yield 6.8 g of the desired product. Rf = 0.28 (in chloroform:isopropanol:ammonia=30:1 :1 ). MS: 476.7 (M+2H+).
  • 22
  • C30H56N2O8 [ No CAS ]
  • [ 156897-06-2 ]
  • [ 922724-99-0 ]
YieldReaction ConditionsOperation in experiment
With dicyclohexyl-carbodiimide; In tetrahydrofuran; at 0 - 20℃; for 10.5h; Example 12: Compound 9; A solution of 1.5 g of M6 in 6 ml of THF was cooled to 00C and 1.4 g of <strong>[156897-06-2]licofelone</strong> were added under rapid stirring, followed by 770 mg of DCC. The mixture was kept at the same temperature for 30 min and then allowed to come to ambient temperature. After another 10 h the mixture was filtered and the filtrate concentrated in vacuum. The residue was chromatographed on silica gel, elution with chloroform:isopropanol: ammonia (7 M in methanol) 40:1 :1 to yield 1.7 g of the desired product, Rf = 0.40 (chloroform:isopropanol:ammonia=30:1 :1 ). MS: 467.7 (M+2H+). EPO <DP n="32"/>
  • 23
  • [ 586410-99-3 ]
  • [ 156897-06-2 ]
  • [ 922724-93-4 ]
YieldReaction ConditionsOperation in experiment
With dicyclohexyl-carbodiimide; In tetrahydrofuran; at 0 - 20℃; for 12.5h; Example 6: Compound 4; EPO <DP n="27"/>In a round bottom flask 5.9 g of M2 were suspended in 20 ml of dry THF. The mixture was cooled to 0-50C in an ice bath and 5.2 g of <strong>[156897-06-2]licofelone</strong> (ML3000) were added, immediately followed by 2.8 g of DCC. The mixture was stirred rapidly for 0.5 h at the same temperature and then the ice bath was removed. The mixture was stirred for another 12 h at ambient temperature and then filtered. The residue was washed with 20 ml of dichloromethane. All volatiles were removed in vacuum. The residue was taken up in 5 ml of toluene and 5 ml of dichloromethane and transferred on a column of silica gel, 25 cm x 4.5 cm, packed as a slurry in dichloromethane:isopropanol: ammonia (7 M in methanol) 100:1 :1. As eluent 400 ml of dichloromethane: isopropanokammonia (7 M in methanol) 60:1 :1 , changing to dichloromethane: isopropanol:ammonia (7 M in methanol) 30:1 :1 were used. The collected fractions containing the product were evaporated at reduced pressure with a bath temperature not exceeding 300C to yield 6.8 g of the desired product.
  • 24
  • C39H74N2O13 [ No CAS ]
  • [ 156897-06-2 ]
  • [ 922724-97-8 ]
YieldReaction ConditionsOperation in experiment
With dicyclohexyl-carbodiimide; In tetrahydrofuran; at 0 - 20℃; for 10.5h; Example 10: Compound 7; EPO <DP n="30"/>A solution of 670 mg of M4 in 4 ml of dry THF was cooled to 0 0C and 600 mg of <strong>[156897-06-2]licofelone</strong> were added under stirring, followed by 290 mg of DCC. After 30 min the mixture was allowed to come to ambient temperature and stirred for another 10 h. The mixture was filtered and the residue concentrated in vacuum, chromatographed on silica gel, elution with chloroform:isopropanol:ammonia (7 M in methanol) 40:1 :1 to yield 0.75 g of the desired product. Rf = 0.67 (chloroform:isopropanol:ammonia=30:1 :1 ). MS: 570.7 (M+2H+).
  • 25
  • C39H74N2O13 [ No CAS ]
  • [ 156897-06-2 ]
  • [ 922724-98-9 ]
YieldReaction ConditionsOperation in experiment
With dicyclohexyl-carbodiimide; In tetrahydrofuran; at 0 - 20℃; for 10.5h; Example 11 : Compound 8; A solution of 430 mg of M5 in 4 ml of dry THF was cooled to 0C and 600 mg of <strong>[156897-06-2]licofelone</strong> were added under stirring, followed by 290 mg of DCC. After 30 min the mixture was allowed to come to ambient temperature and stirred for another 10 h. The mixture was filtered and the residue concentrated in vacuum, chromatographed on silica gel, elution with chloroform:isopropanol:ammonia (7 M in methanol) 40:1 :1 to yield 0.75 g of the desired product, Rf = 0.41 (chloroform:isopropanol:ammonia=30:1 :1 ). MS: 570.7 (M+2H+).
  • 26
  • [ 79-37-8 ]
  • [ 133111-56-5 ]
  • [ 156897-06-2 ]
YieldReaction ConditionsOperation in experiment
6. 6-(4-chlorophenyl)-2.2-dimethyl-7-phenyl-2.3-dihydro-l-H-pyrrolizin-5-yl-acetic acid (ML-3000).2^ 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-l-H-pyrrolizine (50 g,0.156 M) is dissolved with stirring in dry tetrahydrofuran. The assembly is blanketed with nitrogen atmosphere. The yellow colored solution is cooled to 10-15 0C and oxalyl chloride (31.6g, 0.24 M) is slowly added over a period of 10-15 min, such that the internal temperature is below 15 0C. After complete addition the green colored solution is <n="12"/>stirred at 18-25 0C for 20-30 min. The reaction mixture is then quenched carefully in Ice (80 g) such that the internal temperature does not exceed above 20 0C. The reaction mixture is then stirred at 20-30 0C for 5-10 min. The solution is diluted with diethylene glycol (27Og) and hydrazine (65g, 1.28 mol). The internal temperature is then raised gradually and solvent THF is distilled off during the process until the temperature reaches75-80 0C. The suspension is then cooled to 50-55 0C and KOH (113 g, 2.02 M) is added portion wise over a period of 30 min. The now yellowish liquid is then heated to 95-110 0C gradually. During the process excessive frothing is observed. Nitrogen is blown through the reaction mixture by means of a dip tube at an increased stirring speed. The temperature is then raised slowly to 140-145 0C and during the process aqueous distillate is collected. The batch is held at 130-145 0C for 2-3 hr. The reaction temperature is then cooled to 35-40 0C and water and diethyl ether are added. The mixture is stirred vigorously for 15-20 min and with the stirring switched off the layers are allowed to settle. The aqueous phase is separated cooled below 5 0C and acidified to pH 1 using a solution of HCl maintaining temperature below 10 0C. The separated solid is taken up in diethyl ether and "the ethereal extract is washed thoroughly with water. The ethereal extract is charcoalised before being evaporated under vacuo below 20 0C. The solid is slurried in heptane and is filtered under suction and washed with heptane. The product is dried in vacuum at 45^-55 0C.
  • 27
  • [ 262426-70-0 ]
  • [ 156897-06-2 ]
YieldReaction ConditionsOperation in experiment
60% The mixture of the ester (IVc) ( 0.5 g, 1.2 mmol), ethanol (5 ml) and 50% NaOH (1 ml) was stirred under slight reflux for 8 hours. Then the mixture was poured into diluted hydrochloric acid (25 ml) and extracted with (3x5 ml). The combined extracts were dried with magnesium sulfate, evaporated until dryness and the evaporation residue was re-crystallized from ethanol. The desired product (I) was obtained in the yield of 60%.
  • 28
  • [ 1061179-20-1 ]
  • [ 156897-06-2 ]
YieldReaction ConditionsOperation in experiment
71% 2-(6-(4-Chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl)acetic acid (I)Carrying out the procedure described in example 17 using the ester (IVb) the desired product (I) was obtained in the yield of 71%.
  • 29
  • [ 156897-06-2 ]
  • C22H22ClN [ No CAS ]
  • 30
  • [ 1061179-22-3 ]
  • [ 156897-06-2 ]
YieldReaction ConditionsOperation in experiment
50% To the solution of the amide (IX) (0.2 g, 0.52 mmol) in methanol (20 ml), heated up to slight reflux, 0.2 ml of sulfuric acid was added and the mixture was refluxed for 4 hours. Subsequently, 40% aqueous solution of sodium hydroxide (2 ml) was added to the reaction mixture and the mixture was further refluxed for 4 hours. Then, the reaction mixture was poured into diluted hydrochloric acid (50 ml) and extracted with ether (3x10 ml). The combined extracts were dried with magnesium sulfate, evaporated until dryness and the evaporation residue was re-crystallized from ethanol. The desired product (I) was obtained in 50% yield.
  • 31
  • [ 123-41-1 ]
  • [ 156897-06-2 ]
  • [ 1224948-00-8 ]
YieldReaction ConditionsOperation in experiment
87% In ethanol; water; at 75 - 77℃;Industry scale;Product distribution / selectivity; <strong>[156897-06-2]Licofelone</strong> (2.45 kg) was slurried in ethanol (6.6 I). The slurry was heated to 75C. 50% aqueous choline (1.65 kg) was introduced maintaining the temperature at 75C and the line was rinsed with ethanol (3.2 I). The resulting solution was stirred at reflux (77C) for 30 min, filtered on a 0.3 mum cartridge filter and the filter was rinsed with warm ethanol (2.5 I). The solution was cooled to 35C and diethylether (19.3 I) was added in 15 min maintaining the temperature at 35C. Diethylether (30.9 I) was added in 30 min keeping the temperature at 35C. The suspension was cooled in 2 h to 23C, stirred at this temperature for about 15 h, further cooled to -13C in 1 h and stirred at this temperature for 2 h. The product was centrifuged and the cake was washed with cold diethylether (7.7 I). The wet cake was dried at approx. 300C for 72 h. Yield: 2.7 kg (=87%), chemical purity (HPLC): 99.84% (water content: 3.5 %)X-ray diffraction diagram and I R-spectrum of the choline salt are shown in Figures 1 B and 2, respectively.
  • 32
  • [ 156897-06-2 ]
  • [ 77-86-1 ]
  • 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-ylacetic acid tromethamine salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
92% In ethanol; at 47℃;Industry scale; <strong>[156897-06-2]Licofelone</strong> (2.25 kg) was slurried in ethanol (59.2 I). The slurry was heated to 47C until dissolution. Tromethamol (0.79 kg) was introduced maintaining the temperature at 47C and the resulting slurry was stirred at 47C for 1 h. Diisopropylether (14.8 I) was added in 15 min maintaining the temperature at 47C. The suspension was cooled in 3 h to 27C, stirred at this temperature for about 1 h, further cooled to -13C in 1 h and stirred at this temperature for 2 h. The product was centrifuged and the cake was washed with cold diisopropylether (7.1 I). The wet cake was dried at approx. 800C for 15 h.Yield: 2.73 kg (= 92%), chemical purity (HPLC): >99.9% (water content: 0.1 %)X-ray diffraction diagram and IR-spectrum of the tromethamine salt are shown in Figures 3 and 4, respectively.
  • 33
  • [ 1003-85-6 ]
  • [ 156897-06-2 ]
  • 35
  • [ 103804-80-4 ]
  • [ 156897-06-2 ]
  • 36
  • [ 126-30-7 ]
  • [ 156897-06-2 ]
  • 38
  • [ 110-52-1 ]
  • [ 156897-06-2 ]
  • [ 912341-47-0 ]
  • 39
  • [ 1310936-45-8 ]
  • [ 156897-06-2 ]
  • 40
  • [ 24772-63-2 ]
  • [ 156897-06-2 ]
  • [ 1332505-35-7 ]
  • 41
  • [ 3344-70-5 ]
  • [ 156897-06-2 ]
  • [ 1332505-36-8 ]
  • 42
  • [ 100-44-7 ]
  • [ 156897-06-2 ]
  • 43
  • [ 106-93-4 ]
  • [ 156897-06-2 ]
  • [ 1025054-99-2 ]
  • 44
  • [ 109-64-8 ]
  • [ 156897-06-2 ]
  • [ 1332505-34-6 ]
  • 45
  • [ 156897-06-2 ]
  • [ 1025055-02-0 ]
  • 46
  • [ 156897-06-2 ]
  • [ 1025055-10-0 ]
  • 47
  • [ 156897-06-2 ]
  • [ 586347-53-7 ]
  • 48
  • [ 156897-06-2 ]
  • [ 1332505-37-9 ]
  • 49
  • [ 156897-06-2 ]
  • [ 1332505-38-0 ]
  • 50
  • [ 6066-82-6 ]
  • [ 156897-06-2 ]
  • licofelone-NHS [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; The synthesis of LFA-9 was achieved in a two-step synthetic strategy (FIG. 1). First, to a solution of <strong>[156897-06-2]licofelone</strong> (28.45 g, 75 mmol) in dichloromethane (CH2C12) (300 mL) was added N-hydroxysuccinimide (NHS) (9.50g, 82.5 mmol) in dichloromethane (300 mL) and N, N'-dicyclohexylcarbodiimide (DCC) (17.03 g, 82.5 mmol ) in dichloromethane (100 mL). The reaction mixture was stirred at room temperature (RT) for overnight. The progress of the reaction was monitored by TLC. After completion of reaction, N, iV'-dicyclohexylurea (a byproduct) was filtered on a sintered funnel and filtrate was evaporated on a rotary evaporator under reduced pressure to obtain <strong>[156897-06-2]licofelone</strong>-NHS in a quantitative yield. This compound was used immediately for the next step without further purification. Second, to a solution of <strong>[156897-06-2]licofelone</strong>-NHS (35.79 g, 75 mmol) in N,N-dimethylformamide (DMF) (650 mL) was added glycine (5.63 g, 75 mmol ) in 0.2M Na2HP04 (100 mL, pH 8.0). The reaction mixture was stirred at room temperature for overnight. The progress of the reaction was monitored by TLC. After completion of reaction, solvents were evaporated on a rotary evaporator under reduced pressure, and the product was extracted into ethyl acetate (2 x 300 mL). The combined organic layer was washed with water (2 x 100 mL) and with brine (2 x 100 mL). The organic layer was dried over sodium sulfate and solvents were evaporated on a rotary evaporator under reduced pressure to obtain the crude LFA-9. The crude compound was purified on a silica gel column by eluting with ethyl acetate to obtain the pure LFA-9 as a white solid (16.50 g, 50.3 %). Alternatively, the crude compound was purified by recrystallization using ethyl acetate/hexane solvent mixture (26.40 g, 80.51 %).
  • 51
  • (E)-but-2-enedioic acid 2-(2-hydroxyethoxy)ethyl ester methyl ester [ No CAS ]
  • [ 156897-06-2 ]
  • (E)-but-2-enedioic acid 2-(2-{2-[2-(4-chlorophenyl)-6,6-dimethyl-1-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl]acetoxy}-ethoxy)ethyl ester methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.01 g With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 1.5h; 1 g (2.6 mmol) 6- (4-chlorophenyl)-2,2-dimethyl-7 -phenyl-2,3 -dihydro- 1 Hpyrrolizin-5-yl] acetic acid (<strong>[156897-06-2]Licofelone</strong>), 0,6 g (3.2 mmol) EDCxHC1, 0.02 g (0.1 mmol) 4-(dimethylamino)pyridine (DMAP) and 0.632 g (2.9 mmol) (E)-But2-enedioic acid 2-(2-hydroxy-ethoxy)-ethyl ester methyl ester (were dissolved in THF (10 ml). The reaction mixture was kept under continuous stirring at roomtemperature for -1.5 h. Stirring was stopped (bright yellow solution with a syrupy white precipitate) and the solvent was evaporated yielding a bright yellow syrup. Water (50 ml) was added and the aqueous layer was extracted with ethylacetate 3 times (3x100 ml). The solvent was evaporated and the crude product subjected to flash chromatography (dichloromethane/MeCN 4:1) to yield the product as yellowoil, which was dried at 7x10-2 mbar at rt for 5 hours to afford the product as yellow syrupy product (1.01 g; 1.7 mmol).?H NMR (400 MHz, acetone-d6) oe [ppm]: 1.28 - 1.32 (m, 6 H) 2.79 - 2.83 (m, 2 H)3.58 (s, 2 H) 3.72 - 3.80 (m, 7 H) 3.82 (s, 2 H) 4.24 - 4.28 (m, 2 H) 4.32 - 4.35 (m,2 H) 6.79 (s, 2 H) 7.03 - 7.07 (m, 3 H) 7.14 - 7.19 (m, 4 H) 7.30 (d, J=8.21 Hz, 2H)LC-MS: tr: 13.5 mm.; m/z: 580 [M+H] (method B)
1.01 g With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 1.5h; Example 7: (E)-But-2-enedioic acid 2-(2-{2-[2-(4-chloro-phenyl)-6,6-dimethyl- l-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl]-acetoxy}-ethoxy)-ethyl ester methyl ester (0163) (0164) 1 g (2.6 mmol) 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro- lH- pyrrolizin-5-yl] acetic acid (<strong>[156897-06-2]licofelone</strong>), 0.6 g (3.2 mmol) EDCxHCl, 0.02 g (0.1 mmol) 4-(dimethylamino)pyridine (DMAP) and 0.632 g (2.9 mmol) (E)-But- 2-enedioic acid 2-(2-hydroxy-ethoxy)-ethyl ester methyl ester (were dissolved in THF ( 10 ml). The reaction mixture was kept under continuous stirring at room temperature for - 1.5 h. Stirring was stopped (bright yellow solution with a syrupy white precipitate) and the solvent was evaporated, yielding a bright yellow syrup. Water (50 ml) was added and the aqueous layer was extracted with ethyl acetate 3 times (3x100 ml). The solvent was evaporated and the crude product subjected to flash chromatography (dichloromethane/MeCN 4: 1 ) to yield the product as yellow oil, which was dried at 7x 10" mbar at RT for 5 hours to afford the product as a yellow syrupy product (1.01 g; 1.7 mmol). 1H NMR (400 MHz, acetone- d6) delta [ppm] : 1.28 - 1.32 (m, 6 H) 2.79 - 2.83 (m, 2 H) 3.58 (s, 2 H) 3.72 - 3.80 (m, 7 H) 3.82 (s, 2 H) 4.24 - 4.28 (m, 2 H) 4.32 - 4.35 (m, 2 H) 6.79 (s, 2 H) 7.03 - 7.07 (m, 3 H) 7.14 - 7.19 (m, 4 H) 7.30 (d, J=8.21 Hz, 2 H) (0165) LC-MS: tr: 13.5 min.; m/z: 580 [M+H]+ (method B)
  • 52
  • (E)-but-2-enedioic acid 2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethyl ester methyl ester [ No CAS ]
  • [ 156897-06-2 ]
  • (E)-but-2-enedioic acid 2-{2-[2-(2-{2-[2-(4-chlorophenyl)-6,6-dimethyl-1-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl]-acetoxy}ethoxy)ethoxy]ethoxy}ethyl ester methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.1 g With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; 1 g (2.6 mmol) 6- (4-chlorophenyl)-2,2-dimethyl-7 -phenyl-2,3 -dihydro- 1 H-pyrrolizin-5-yl]acetic acid (<strong>[156897-06-2]Licofelone</strong>), 0.6 g (3.2 mmol) EDCxHC1, 20 mg (0.1 mmol) DMAP and 0.89 g (2.9 mmol) (E)-But-2-enedioic acid 2-{2-[2-(2- hydroxy-ethoxy)-ethoxy]-ethoxy}-ethyl ester methyl ester were dissolved in 30 ml THF. During 0/N stirring at RT, a bright yellow solution with a syrupy white precipitate was formed. The solvent was evaporated, to the bright yellow syrup50 ml water were added and the aqueous layer was extracted with 3x100 ml ethyl acetate. The organic layers were combined, solvent was evaporated and the crude product subjected to flash chromatography (ethyl acetate/n-heptane 50:50 (v/v)) to yield the product as yellow oil, which was dried at 17 mbar at room temperature for 5 hours to afford the product as yellow syrupy product (1.1 g; 1.6 mmol).?H NMR (400 MHz, CDC13) oe [ppm]: 1.29 (s, 6 H) 2.16 (s, 1 H) 2.84 (s, 2 H) 3.55(s, 2 H) 3.63 (d, J=2.35 Hz, 8 H) 3.68 - 3.76 (m, 6 H) 3.80 (s, 3H) 4.25 - 4.30 (m,2 H) 4.32 - 4.36 (m, 2 H) 6.88 (s, 2 H) 7.02 - 7.09 (m, 3 H) 7.11 - 7.15 (m, 2 H)7.18 (s, 2 H) 7.21 -7.27 (m, 2 H)LC-MS: tr: 12.3 mm.; m/z: 688 [M+H] (method C)
1.1 g With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; Example 3: (E)-But-2-enedioic acid 2-{2-[2-(2-{2-[2-(4-chloro-phenyl)-6,6- dimethyl-l-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl]-acetoxy}-ethoxy)-ethoxy]- ethoxy}-ethyl ester methyl ester (0135) (0136) 1 g (2.6 mmol) 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro- lH- pyrrolizin-5-yl] acetic acid (<strong>[156897-06-2]licofelone</strong>), 0.6 g (3.2 mmol) EDCxHCl, 20 mg (0137) (0.1 mmol) DMAP and 0.89 g (2.9 mmol) (E)-But-2-enedioic acid 2- { 2-[2-(2- hydroxy-ethoxy)-ethoxy] -ethoxy} -ethyl ester methyl ester were dissolved in 30 ml THF. During O/N stirring at RT, a bright yellow solution with a syrupy white precipitate was formed. The solvent was evaporated, to the bright yellow syrup 50 ml water were added and the aqueous layer was extracted with 3x 100 ml ethyl acetate. The organic layers were combined, the solvent was evaporated and the crude product subjected to flash chromatography (ethyl acetate : n-heptane 50 : 50 (v/v)) to yield the product as yellow oil, which was dried at 17 mbar at room temperature for 5 hours to afford the product as yellow syrupy product ( 1.1 g; 1.6 mmol). (0138) 1H NMR (400 MHz, CDC13) delta [ppm] : 1.29 (s, 6 H) 2.16 (s, 1 H) 2.84 (s, 2 H) 3.55 (s, 2 H) 3.63 (d, J=2.35 Hz, 8 H) 3.68 - 3.76 (m, 6 H) 3.80 (s, 3H) 4.25 - 4.30 (m, (0139) 2 H) 4.32 - 4.36 (m, 2 H) 6.88 (s, 2 H) 7.02 - 7.09 (m, 3 H) 7.1 1 - 7.15 (m, 2 H) 7.18 (s, 2 H) 7.21 - 7.27 (m, 2 H) (0140) LC-MS: tr: 12.3 min.; m/z: 688 [M+H]+ (method C)
  • 53
  • [ 112-60-7 ]
  • [ 156897-06-2 ]
  • [2-(4-chlorophenyl)-6,6-dimethyl-1-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl]-acetic acid 2-{2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethoxy}-ethyl ester [ No CAS ]
  • [2-(4-chlorophenyl)-6,6-dimethyl-1-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl]-acetic acid 2-{2-[2-(2-{2-[2-(4-chlorophenyl)-6,6-dimethyl-1-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl]-acetoxy}-ethoxy)-ethoxy]-ethoxy}-ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.06 g; 0.76 g With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; for 6h; Example 4a: [2-(4-Chloro-phenyl)-6,6-dimethyl-l-phenyl-6,7-dihydro-5H- pyrrolizin-3-yl] -acetic acid 2-{2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethoxy}-ethyl ester (4a) and Reference Example 4b: [2-(4-Chloro-phenyl)-6,6-dimethyl-l-phenyl-6,7-dihydro- 5H-pyrrolizin-3-yl]-acetic acid 2-{2-[2-(2-{2-[2-(4-chloro-phenyl)-6,6-dimethyl-l- phenyl-6,7-dihydro-5H-pyrrolizin-3-yl]-acetoxy}-ethoxy)-ethoxy]-ethoxy}-ethyl ester (4b) (0141) (0142) 1.53 g (7.9 mmol) tetraethylenglykol, 1.21 g (6.3 mmol) EDCxHCl, 30 mg (0.3 mmol) DMAP and 2 g (5.3 mmol) 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro- lH-pyrrolizin-5-yl] acetic acid (<strong>[156897-06-2]licofelone</strong>) were dissolved in 40 ml THF. The reaction mixture was stirred for 6 hours. Stirring was stopped (bright yellow solution with a syrupy white precipitate) and the organic layer was decanted off from the syrupy product. To the residue 40 ml THF were added and the mixture was stirred for 1 minute before being decanted off again. The solvent of the combined THF layers was evaporated, yielding a yellow syrup. The crude product contained two major products, 4a and 4b. After flash chromatography (gradient: ethyl acetate/n-heptane 1 :2 (v/v) -> ethyl acetate/n-heptane 2: 1 -> ethyl acetate (100%) to yield the above products: (0143) 4b (0.76 g (0.8 mmol)) was obtained as a colorless solid (Rf (ethyl acetate/n-heptane 2: 1): 0.63). The product was dried at 7x10" mbar at RT for 2 hours. (0144) 1H NMR (400 MHz, acetone- d6) delta [ppm] : 1.29 (s, 12 H) 2.80 - 2.82 (m, 5 H) 3.55 (s, 4 H) 3.58 (s, 8 H) 3.66 - 3.70 (m, 4 H) 3.81 (s, 4 H) 4.20 - 4.26 (m, 4 H) 7.02 -7.07 (m, 6 H) 7.14 - 7.19 (m, 8 H) 7.29 (d, J=8.21 Hz, 4 H) LC-MS: tr: 15.0 min.; m/z: 917 [M+H]+ (method D) (0145) 4a (Rf EtOAc/H 2/1 : 0.12) was obtained as slightly brown to yellow oil. After a second chromatography (silica, 100% ethyl acetate), 4a was obtained as a yellow oil (1.06 g; 0.8 mmol). The product was dried at 7x10" mbar at RT for 2 hours. (0146) 1H NMR (400 MHz, acetone- d6) delta [ppm] : 1.30 (s, 6 H) 2.79 - 2.84 (m, 3 H) 3.44 - 3.56 (m, 3 H) 3.57 (s, 6 H) 3.59 - 3.61 (m, 5 H) 3.69 - 3.72 (m, 2 H) 3.83 (s, 2 H) 4.23 - 4.27 (m, 2 H) 7.03 - 7.08 (m, 3 H) 7.14 - 7.20 (m, 4 H) 7.31 (d, J=8.60 Hz, 2 H) (0147) LC-MS: tr: 10.7 min.; m/z: 556 [M+H]+ (method D)
  • 54
  • [ 107-21-1 ]
  • [ 156897-06-2 ]
  • 2-hydroxyethyl 2-[2-(4-chlorophenyl)-6,6-dimethyl-1-phenyl-5,7-dihydropyrrolizin-3-yl]acetate [ No CAS ]
  • 2-[2-[2-(4-chlorophenyl)-6,6-dimethyl-1-phenyl-5,7-dihydropyrrolizin-3-yl]acetyl]oxyethyl-2-[2-(4-chlorophenyl)-6,6-dimethyl-1-phenyl-5,7-dihydropyrrolizin-3-yl]acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 48h; Example 5a: 2-hydroxyethyl 2-[2-(4-chlorophenyl)-6,6-dimethyl-l-phenyl-5,7- dihydropyrrolizin-3-yl]acetate (and (0149) Reference Example 5b: 2-[2-[2-(4-chlorophenyl)-6,6-di-methyl-l-phenyl-5,7- dihydropyrrolizin-3-yl]acetyl]oxyethyl-2-[2-(4-chloro-phenyl)-6,6-dimethyl-l- phenyl-5,7-dihydropyrrolizin-3-yl]acetate (0150) (0151) In a 100 ml RBF, 1.77 ml (31.6mmol) ethylene glycol, l,82g (9,5 mmol) EDCxHCl and 50 mg (0.4 mmol) DMAP were dissolved in 20 ml THF. 3 g (7.9 mmol) (2.6 mmol) 6- (4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro- lH-pyrrolizin-5-yl] acetic acid (<strong>[156897-06-2]licofelone</strong>) dissolved in 30 ml THF were dropped into this solution within 55 min. The reaction mixture was kept under continuous stirring at RT for two days. Stirring was stopped and the solvent was evaporated. The crude product contained two major products, 5a and 5b. Separation was achieved by flash chromatography (ethyl acetate/n-heptane 50:50 (v/v)). (0152) Fraction 1 contained compound 5b, which was obtained as a slightly yellow oil after solvent evaporation. After addition of 30 ml n-pentane and overnight stirring, a white precipitate was obtained, which was filtered off and dried for 1 hour at 50C and 23 mbar. (0153) 1H-NMR (400 MHz, DMSO- 6) delta ppm: 1.17 (s, 6 H) 2.75 (s, 2 H) 3.53 (s, 2 H) 3.67 (s, 2 H) 4.29 (s, 2 H) 6.94 (d, J=7.43 Hz, 2 H) 6.99 - 7.06 (m, 3 H) 7.14 (t, J=7.04 Hz, 2 H) 7.27 (d, J=8.21 Hz, 2 H) (0154) LC-MS (ESI+): m/z 785 [M+H]+ (0155) Fraction 2 contained compound 5a, which solidified as a foam after solvent evaporation. (0156) 1H-NMR (400 MHz, DMSO-d6) delta ppm: 1.21 (s, 6 H) 2.76 (br. s., 2 H) 3.53 (br. s., 2 H) 3.56 (d, J=4.69 Hz, 2 H) 3.72 (br. s., 2 H) 4.02 - 4.12 (m, 2 H) 4.75 - 4.85 (m, 1 H) 6.91 - 6.99 (m, 2 H) 7.00 - 7.10 (m, 3 H) 7.12 - 7.20 (m, 2 H) 7.27 - 7.35 (m, 2 H) (0157) LC-MS (ESI+): m/z 424 [M+H]+
  • 55
  • [ 156897-06-2 ]
  • [ 100-79-8 ]
  • rac-[2-(4-chloro-phenyl)-6,6-dimethyl-1-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl]-acetic acid 2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 3h; Step 1 : Synthesis of rac-[2-(4-chloro-phenyl)-6,6-dimethyl-l-phenyl-6,7-dihydro-5H- pyrrolizin-3-yl] -acetic acid 2,2-dimethyl-[l,3]dioxolan-4-ylmethyl ester (0169) 1.74 g (13.2 mmol) rac-(2,2-dimethyl-[l,3]dioxolan-4-yl)-methanol, 1.82 g (9.5 mmol) EDCxHCl and 0.05 g (0.4 mmol) DMAP were dissolved in 15 ml THF. 3 g (7.9 mmol) 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro- lH-pyrrolizin-5-yl] acetic acid (<strong>[156897-06-2]licofelone</strong>) dissolved in 20 ml THF were dropped into this solution within 15 min. The reaction mixture was kept under continuous stirring at RT for 3 hours. Stirring was stopped and the solvent was decanted off. The decanted organic layer was evaporated and the obtained yellow oily product was subjected to flash chromatography (ethyl acetate/n-heptane 1 :2 (v/v)) to yield the oily product. To the yellow oil 50 ml n- pentane were added while stirring. A slightly yellow to white solid precipitated. After stirring for 1 hour, the product was filtered off and dried for 2 hours at RT at 21 mbar. (0170) 1H NMR (400 MHz, acetone- d6) delta [ppm] : 1.30 (s, 5 H) 1.34 (s, 1 H) 2.80 - 2.83 (m, 1 H) 3.60 (s, 1 H) 3.74 (dd, J=8.41, 6.06 Hz, 0.5 H) 3.82 (s, 1 H) 4.07 (dd, J=8.21, 6.65 Hz, 0.5 H) 4.17 (dd, J=5.08, 3.52 Hz, 1 H) 4.32 (d, J=4.69 Hz, 0.5 H) 7.03 - 7.07 (m, 1 H) 7.15 - 7.19 (m, 2 H) 7.30 (d, J=8.21 Hz, 1 H)
  • 56
  • [ 156897-06-2 ]
  • O4-[2-[2-[2-(4-chlorophenyl)-6,6-dimethyl-1-phenyl-5,7-dihydropyrrolizin-3-yl]acetyl]oxyethyl] O1-methyl (E)-but-2-enedioate [ No CAS ]
  • 57
  • [ 118-42-3 ]
  • [ 156897-06-2 ]
  • HL [ No CAS ]
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