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Chemical Structure| 1256388-51-8
Chemical Structure| 1256388-51-8
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Product Details of [ 1256388-51-8 ]

CAS No. :1256388-51-8 MDL No. :MFCD25976756
Formula : C49H54F2N8O6 Boiling Point : -
Linear Structure Formula :- InChI Key :VRTWBAAJJOHBQU-KMWAZVGDSA-N
M.W : 889.00 Pubchem ID :67505836
Synonyms :
GS-5885

Safety of [ 1256388-51-8 ]

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 [ 1256388-51-8 ]

* 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 [ 1256388-51-8 ]

[ 1256388-51-8 ] Synthesis Path-Downstream   1~58

  • 1
  • [ 1256393-27-7 ]
  • [ 111398-44-8 ]
  • [ 1256388-51-8 ]
YieldReaction ConditionsOperation in experiment
76 mg Preparation of (1-{3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl- butyi7l)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1 H- benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)- carbamic acid methyl ester 6. 3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza- spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1 H-benzoimidazol-2-yl]-2-aza- bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester 614 (115 mg, 0.138 mmol) was dissolved in methylene chloride (2 mL) and HCI in dioxane (4M, 2 mL) was added and stirring at room temperature was continued. After 20 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (1.5 mL) and DIEA (53.4 mg, 0.414 mmol) was added. A solution of 2- (L) Methoxycarbonylamino-3-methyl-butyric acid 611 (24.2 mg, 0.138 mmol), HATU (52.4 mg, 0.138 mmol) and DIEA (17.8 mg, 0.138 mmol) in DMF (1 mL) was added. The reaction was stirred at room temperature. After 20 minutes, the reaction was diluted with EtOAc and was washed with aqueous bicarbonate solution, aqueous LiCI solution (5%), brine, and was dried over sodium sulfate. Filtration and removal of solvents in vacuo gave the crude material, which was purified by RP-HPLC (eluent: water / MeCN w/ 0.1% TFA) to yield compound 6 (76 mg). LCMS-ESI+: calc'd for C49H54F2N806: 888.9 (M +); Found: 890.0 (M+H+). H-NMR: 300 MHz, (dmso-de) delta: 8.20-7.99 (m, 8H), 7.73 (s, 2H), 7.37 - 7.27 (m, 2H), 5.25 (dd, J = 7.2 Hz, 1 H), 4.78 (s, 1H) 4.54 (s, 1 H), 4.16 (m, 1 H), 4.02 (m, 1H), 3.87 (m,1H), 3.74 (m, 1 H), 3.55 (s, 3H), 3.53 (s, 3H), 2.75 (m, 1H), 2.25 (m, 2H), 2.09 - 2.04 (m, 2H), 1.88 - 1.79 (m, 2H), 1.54 (m, 1 H), 0.94 - 0.77 (m, 15H) 0.63 (m, 4H) ppm. 9F-NMR: 282 MHz, (dmso-d6) delta: -109.1 ppm [- 74.8 ppm TFA].
  • 2
  • [ 111398-44-8 ]
  • [ 1256388-51-8 ]
  • 3
  • [ 1256388-49-4 ]
  • [ 1256388-51-8 ]
  • 5
  • C35H32F2N6*4ClH [ No CAS ]
  • [ 1256388-51-8 ]
  • 6
  • (1R,3S,4S)-tert-butyl 3-(6-(7-(2-((S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptan-6-yl)-1H-imidazol-5-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate [ No CAS ]
  • [ 1256388-51-8 ]
  • 7
  • (1-{3-[6-(9,9-difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]2-aza-bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)carbamicacid methyl ester acetone salt [ No CAS ]
  • [ 1256388-51-8 ]
YieldReaction ConditionsOperation in experiment
82% In water; acetonitrile; at 23℃; for 0.5h; C. Isolation of Amorphous Compound I [0266] The acetone solvate of Compound I, Compound 31 (191.4 g), was combined with acetonitrile (1356 g) in a reaction vessel and mixed until a solution was formed. This solution was slowly added to another reaction vessel containing vigorously agitated water (7870 g). The combined reaction mixture was agitated at about 23 C. for about 30 minutes. The solid was then filtered and dried at about 40-45 C. to afford amorphous Compound I (146.4 g, 82% yield).
  • 8
  • [ 147-71-7 ]
  • [ 1256388-51-8 ]
  • (1-{3-[6-(9,9-difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]2-aza-bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)carbamicacid methyl ester D-tartrate salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
65.6% In ethyl acetate; at 23 - 50℃; for 16h; 6) As shown in equation , the reaction flask was added the formula (ix) Compound (10g, 11.2mmol) and ethyl acetate (70mL) mixed, stirred and dissolved at 50 deg.] C; the other D- tartaric acid (D-Tartaricacid) ( 1.5g, 10mmol) was dissolved in ethanol (70mL), and added dropwise to the above formula and (ix) a compound with a mixed solution of ethyl acetate, 50 precipitated crystals have a slow reaction, after cooling to 23 16h, the reaction was continued at least 3h after filtration, the cake washed with 40ml of a volume ratio of 1: 1 ethanol - ethyl acetate mixture was poured to wash the filter cake was pulled dry to give the formula (ix) of the target product, namely the Leidipawei D- tartrate, is 7.3g, the yield was 65.6%.
at 0 - 20℃; Example 4 Preparation of (1-{3-[6-(9,9-difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid D-tartrate (Compound I D-tartrate) [0183] Approximately 100-500 mg of Compound I Form I was transferred to each of a set of vials containing a magnetic stir bar. To each vial was added approximately 1.0-20 mL of acetonitrile (ACN) or isopropyl alcohol (IPA) until a clear solution was achieved. In a separate set of vials, clear ACN or IPA solutions of the acids listed in Table 4 below were prepared. [0184] Each of the acid solutions was added to a corresponding solution of Compound I in a dropwise fashion until 1 equivalent of acid had been. If resulting suspensions were observed, they were allowed to cool from ambient temperature to 0 C. If clear solutions were observed, they were allowed to slowly evaporate to assess possible crystallization. [0185] Among the acids screened, L-tartaric acid and HCl separately appeared to react with Compound I Form I and gave weak signs of crystallinity, as determined by PLM. However, the solid products from these two reactions proved to be unstable and lost crystallinity easily upon exposure to ambient atmosphere. [TABLE-US-00005] TABLE 4 Salt Screen for Compound I Acid pKa Observations HCl -6 Disordered salt formed Citric acid triacid, 3.1; 4.8; 6.4 No product formed Maleic acid diacid; 1.92; 6.23 Amorphous product L-tartaric acid diacid; 3.02; 4.36 Amorphous product formed D-tartaric acid diacid; 2.93; 4.23 Crystalline product formed fumaric acid diacid, 3.03; 4.38 No product formed Toluene sulfonic acidmonohydrate -1.34 No product formed Benzene sulfonic acid 0.7 No product formed Sulfuric acid -3 No product formed Succinic acid diacid, 4.2; 5.6 No product formed L-Malic acid diacid, 3.46; 5.1 No product formed D-Malic acid diacid, 3.46; 5.1 No product formed Malonic acid diacid, 2.83; 5.69 No product formed Oxalic acid diacid, 1.27; 4.28 amorphous product [0186] Even with a thorough crystalline form screen for L-tartrate, no stable crystalline product was successfully produced, as summarized below in Table 5. XRPD characterization of various samples resulting from the stable form screen for L-tartrate showed that the samples remained as amorphous solids in most solvents. In acetone, Compound I reverted back to the acetone solvate Form I as described above. [TABLE-US-00006] TABLE 5 Crystalline Form Screen Summary for Compound I L-tartrate Solvent 24 hr XRPD 2 week XRPD Observation Water Amorphous solid Amorphous solid Suspension IPAc Amorphous solid Amorphous solid Suspension MTBE Amorphous solid Amorphous solid Suspension 2-propanol Amorphous solid Amorphous solid Suspension THF N/A N/A Clear solution Acetone Compound I Compound I Suspension Form I Form I Methanol N/A N/A Clear solution ACN Amorphous solid Amorphous solid Suspension Ethanol N/A N/A Clear solution Ethyl acetate Amorphous solid Amorphous solid Suspension 2-MeTHF Amorphous solid Amorphous solid Suspension MEK Amorphous solid Amorphous solid Suspension MIBK Amorphous solid Amorphous solid Suspension n-heptane Amorphous solid Amorphous solid Suspension Toluene Amorphous solid Amorphous solid Suspension DCM Amorphous solid Amorphous solid Suspension aw of 0.8(EtOH/water) N/A N/A Clear solution [0187] Following these observations, D-tartaric acid was added to the acid list. Thus, when an IPA solution of D-tartaric acid was added to a solution of Compound I in IPA, a white suspension was generated immediately. A sample was filtered and characterized with XRPD, according to parameters described above, that clearly showed a crystalline product, (1-{3-[6-(9,9-difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid D-tartrate (Compound I D-tartrate). [0188] FIG. 9 shows the XRPD pattern of Compound I D-tartrate. The major peaks and corresponding relative intensities in the XRPD pattern diagram are listed below in Table 6 [TABLE-US-00007] TABLE 6 Major XRPD peaks for Compound I D-tartrate Position (2theta) Relative Intensity 4.0 87.8% 7.9 17.7% 9.1 38.9% 10.3 47.8% 12.7 30.6% 14.8 14.9% 15.8 13.2% 16.2 16.8% 16.9 15.4% 17.5 18.2% 18.3 26.4% 19.2 16.4% 19.7 100.0% 20.8 20.0% 21.0 27.2% 22.8 19.7% 24.0 30.9% 27.4 10.6% 28.2 5.6% [0189] The crystallinity of Compound I D-tartrate was further confirmed by a Polarized Light Microscopic (PLM) image of the crystals. [0190] The DSC curve of Compound I D-tartrate shows that upon heating this crystalline material has one sharp endotherm at 221.08 C., which indicates a clear melting event (FIG. 10). The TGA curve shows minimal weight loss, which indicates that Compound I D-tartrate is anhydrous. Dynamic vapor sorption (DVS) data demonstrated that Compound I D-tartrate tak...
  • 9
  • [ 111398-44-8 ]
  • [ 1256393-27-7 ]
  • [ 1256388-51-8 ]
YieldReaction ConditionsOperation in experiment
76 mg Example 6 Preparation of (1-{3-6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 6 3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester 614 (115 mg, 0.138 mmol) was dissolved in DCM (2 mL) and HCl in dioxane (4M, 2 mL) was added and stirring at room temperature was continued. After 20 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (1.5 mL) and DIEA (53.4 mg, 0.414 mmol) was added. A solution of 2-(L) Methoxycarbonylamino-3-methyl-butyric acid 611 (24.2 mg, 0.138 mmol), HATU (52.4 mg, 0.138 mmol) and DIEA (17.8 mg, 0.138 mmol) in DMF (1 mL) was added. The reaction was stirred at room temperature. After 20 minutes, the reaction was diluted with EtOAc and was washed with aqueous bicarbonate solution, aqueous LiCl solution (5%), brine, and was dried over sodium sulfate. Filtration and removal of solvents in vacuo gave the crude material, which was purified by RP-HPLC (eluent: water/MeCN w/0.1% TFA) to yield compound 6 (76 mg). LCMS-ESI+: calc'd for C49H54F2N8O6: 888.9 (M+). Found: 890.0 (M+H+). 1H-NMR: 300 MHz, (dmso-d6) delta: 8.20-7.99 (m, 8H), 7.73 (s, 2H), 7.37-7.27 (m, 2H), 5.25 (dd, J=7.2 Hz, 1H), 4.78 (s, 1H) 4.54 (s, 1H), 4.16 (m, 1H), 4.02 (m, 1H), 3.87 (m, 1H), 3.74 (m, 1H), 3.55 (s, 3H), 3.53 (s, 3H), 2.75 (m, 1H), 2.25 (m, 2H), 2.09-2.04 (m, 2H), 1.88-1.79 (m, 2H), 1.54 (m, 1H), 0.94-0.77 (m, 15H) 0.63 (m, 4H) ppm. 19F-NMR: 282 MHz, (dmso-d6) delta: -109.1 ppm [-74.8 ppm TFA].
  • 10
  • [ 111398-44-8 ]
  • [ 1256388-51-8 ]
  • 11
  • [ 1256387-73-1 ]
  • [ 1256388-51-8 ]
  • 12
  • C45H48F2N6O4*ClH [ No CAS ]
  • [ 111398-44-8 ]
  • [ 1256388-51-8 ]
  • 13
  • (1R,3S,4S)-methyl 2-((R)-1-phenylethyl)-2-azabicyclo[2.2.1]heptane-3-carboxylate [ No CAS ]
  • [ 1256388-51-8 ]
  • 15
  • (1R,3S,4S)-2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester [ No CAS ]
  • [ 1256388-51-8 ]
  • 17
  • (6S)-6-[5-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-azaspiro[2.4]heptane-5-carboxylic acid 1,1-dimethylethyl ester [ No CAS ]
  • [ 1256388-51-8 ]
  • 18
  • (1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid methyl ester [ No CAS ]
  • [ 1256388-51-8 ]
  • 19
  • [ 1181573-36-3 ]
  • [ 1256388-51-8 ]
  • 20
  • C35H32F2N6*4ClH [ No CAS ]
  • [ 111398-44-8 ]
  • [ 1256388-51-8 ]
YieldReaction ConditionsOperation in experiment
85.4% 5) As shown in equation , the HOBt (1- hydroxybenzotriazole) (5g), Moc-L- Valine (9.6 g of) and DMF (dimethyl formamide) (120mL) added to the reaction flask mixed, stirred and dissolved, was added EDC.HCl (10.5g), after stirring for 30 min, cooled to 0 deg.] C, was added (viii) compound (12g), N- methylmorpholine (12mL) formula, warmed to 25 reaction 4 h, the reaction was added water 6ml 15H overnight, and TLC (eluent PE: EA = 10: 1 mixture) analysis showed the compound of formula (viii) the reaction is complete, add 300ml volume ratio of 1: 1 ethyl acetate acetate - water mixture. after stirring for 1h, liquid separation, the organic phase was washed with 60ml of 5% NaHCO3Washed 10mL * 2 and the combined organic phases, spin dry and dried to give a viscous oil 14g, HPLC show oil which contains HOBt around 6%; oil was dissolved after the DMF was poured into 1L of water to precipitate a solid, pumping It was filtered off, the solid portion was dried, to give a pale yellow solid of formula (ix) compound, i.e. Leidipawei, to 12.3 g, yield 85.4%, HPLC purity 97.3% detection.Show oil was dissolved with DMF and then water was poured into 1L of water beating step can be mixed in the product effectively remove HOBt, to give the desired solid product of high purity.And other organic solvents as reported in the prior art are unable to achieve this effect.
  • 21
  • [ 1129634-44-1 ]
  • [ 1256388-51-8 ]
  • 22
  • (S)-6-(2-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-oxoethyl) 5-tert-butyl 5-azaspiro[2.4]heptane-5,6-dicarboxylate [ No CAS ]
  • [ 1256388-51-8 ]
  • 23
  • 1-(7-bromo-9,9-difluoro-9-hydrofluoren-2-yl)-2-chloroethanone [ No CAS ]
  • [ 1256388-51-8 ]
  • 24
  • C49H54F2N6O9 [ No CAS ]
  • [ 1256388-51-8 ]
YieldReaction ConditionsOperation in experiment
With ammonium acetate; In 2-methoxy-ethanol; toluene; at 100 - 102℃; for 5h; Example 7: Preparation of ledipasvir (Formula 1) The compound of formula 2 (2 g), toluene (20 mL), 2-methoxy ethanol (0.6 g), and ammonium acetate (0.83 g) were charged to a vessel. The reaction mass was maintained for 5 hours at 100-102 C, subsequently cooled to 20-25 C, and charged with ethyl acetate (20 mL). The organic layer was washed with water (2 x 20 mL), followed by 5% sodium bicarbonate solution (20 mL), then water (2 x 20 mL). Finally, the organic layer was distilled under reduced pressure. The residue stirred with acetone (22 mL) for 18 hours at 20-25 C and ledipasvir acetone solvate isolated through filtration with 99.2% (HPLC).
70 g With ammonium acetate; In toluene; at 100℃; In the three-mouth flask in (VI) compound is added to the crude (91g, 96mmol), ammonium acetate (37g, 480mmol), toluene (910 ml), stirring and heating to 100 C reaction 6 - 8 hours. After the reaction cooled to room temperature by adding ethyl acetate (364 ml), washing 2 times (546 ml), sodium sulfate drying, concentrated to remove most of the solvent, the crude approximatelyreddy handkerchief Wei shall be oily thing 70g
  • 25
  • 3-(6-bromo-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane [ No CAS ]
  • [ 1256388-51-8 ]
  • 26
  • [ 1256389-44-2 ]
  • [ 1256388-51-8 ]
  • 27
  • 6-(7-(2-((S)-5-azaspiro[2.4]heptan-6-yl)-1H-imidazol-5-yl)-9,9-difluoro-9H-fluoren-2-yl)-2-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazole [ No CAS ]
  • [ 111398-44-8 ]
  • [ 1256388-51-8 ]
YieldReaction ConditionsOperation in experiment
25 g Methoxycarbonyl L-valine (11.25 g), hydroxybenzotriazole (9.25 g) & l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.25 g) and dichloromethane (250 ml) were charged to a flask. The reaction mixture was agitated for 20 minutes for 23C, and then solution was cooled to 0-5C. 6-(7-(2-((S)-5-azaspiro [2.4] heptan-6-yl)- lH-imidazol-5-yl)-9,9-difluoro-9H-fluoren-2-yl)-2-((lR,3S,4S)-2- azabicyclo[2.2.1]heptan-3-yl)-lH-benzo[d]imidazole (25 g) and add di isopropyl ethylamine (20 g) were added to reaction mixture and contents were stirred for at same temperature and maintained for 4 hours. After complies of reaction, water was added to the reaction mass and separate the two layers. The organic layer was washed with sodium bi carbonate and water. The organic layer was distilled to half of volume and cooled; further acetone was added to the organic layer. The reaction contents were seeded with Ledipasvir (acetone as a solvate) and stirred for 4 hours. The contents were filtered and washed with acetone and the cake was dried to Ledipasvir acetone as a solvate (20-25 g).
  • 28
  • (6S)-6-[4-(7-chloro-9,9-difluoro-9H-fluoren-2-yl)-1-[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole-2-yl]-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester [ No CAS ]
  • [ 1256388-51-8 ]
  • 29
  • C35H32F2N6*BrH [ No CAS ]
  • [ 111398-44-8 ]
  • [ 1256388-51-8 ]
YieldReaction ConditionsOperation in experiment
82.1% (5) 1000 g of dichloromethane, 200 g of HATU and 200 g of MOC-L-valine were charged into a 2 L reactor at 20 CThe mixture was stirred for 30 minutes, cooled to 0 C, 250 g of a compound having the structure represented by the formula VIII was added, and 250 g of triethylAmine, 30 minutes to complete; after adding, the temperature to 20 reaction 3 hours, send sample detection HPLC, with the structure shown in the structure of The content of the content within 0.3% of the reaction end point, or continue to respond to the qualified so far;The product was isolated and purified according to the method of Example 1 to give 253.3 g of the product of leptopine as a white powder,The yield was 82.1% and the purity was 99.5%.
  • 30
  • (6S)-6-(1H-imidazole-2-yl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester [ No CAS ]
  • [ 1256388-51-8 ]
  • 31
  • (6S)-6-(1-[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester [ No CAS ]
  • [ 1256388-51-8 ]
  • 32
  • [ 99586-26-2 ]
  • [ 1256388-51-8 ]
  • 33
  • 2-bromo-7-chloro-9,9-difluoro-9H-fluorene [ No CAS ]
  • [ 1256388-51-8 ]
  • 34
  • C42H43F2N7O3*4ClH [ No CAS ]
  • [ 111398-44-8 ]
  • [ 1256388-51-8 ]
YieldReaction ConditionsOperation in experiment
48 g The compound (VIII) (48g, 64.52mmol), EDCI (29.68g, 154 . 82mmol), HOBt (22.66g, 167 . 73mmol), Moc - L - valine (24.86g, 141 . 92mmol) and N, N - dimethyl formamide 480 ml in three-port flask add and stir to dissolve. The room temperature slowly dropping N - methyl morpholine (42.41g, 419 . 32mmol), the transfusion reaction at room temperature after 6 - 8 hours. Add 50 ml water, reaction at room temperature for 6 - 8 hours. After the reaction by adding 450 ml isopropyl acetate and 600 ml water, liquid, organic phase successively reuse 450 ml water washing, 450 ml 5% sodium bicarbonate washing, 450 ml water washing, drying, and concentrated to obtain oil object reddy handkerchief Wei Cupinreddy handkerchief Wei crude oil by adding acetone 670 ml, stirring and heating to 45 C dissolved, adding little reddy handkerchief Wei acetone compound crystal seeds, slow cooling, a large amount of precipitation of the product. After slow cooling to room temperature to continue stirring 2 hours, filtering, washing the cake with a small amount of acetone, 45 C vacuum dry to get reddy handkerchief Wei acetonide 46g.
  • 36
  • C47H51F2N5O8 [ No CAS ]
  • [ 1256388-51-8 ]
  • 38
  • C42H43F2N7O3 [ No CAS ]
  • [ 1256388-51-8 ]
  • 39
  • [ 1256388-51-8 ]
  • [ 104-15-4 ]
  • ledipasvir ditosylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
10.5 g In ethyl acetate; To lOg of Ledipasvir in 50mL of ethyl acetate; 4.2g of p-toluene sulfonic acid was added and the reaction mixture was stirred. The generated solid was isolated byfiltration and washed with ethyl acetate to obtain 10.5g of ditosylate salt of ledipasvir?H NMR (300MHz), (DMSO-d6,): 8.29-7.89 (9.3H), 7.5 1-7.37 (5.4H), 7.13-7.10 (3.9), 5.27 (1.2H) 4.86 (1.2H), 4.56 (1.2H), 4.22-3.38 (14.4H), 3.087-2.87 (1.4H), 2.5-1.6 (16H), 1.16-0.64 (14H).
  • 40
  • ledipasvir tosylate [ No CAS ]
  • [ 1256388-51-8 ]
YieldReaction ConditionsOperation in experiment
4.5 g With ammonium hydroxide; In water; ethyl acetate; The tosylate salt of compound of formula I was transfened to another RBF containingwater and ethyl acetate. The aqueous ammonia was added to the above mixture andstined. The separated organic layer was washed with water and pH was adjusted to 1.5-3 with HC1. The organic layer was separated and distilled out under vacuum below45C till residue remains in RBF. Acetonitrile was added and organic layer wasdistilled out under vacuum below 45C. Again acetonitrile was added. In another RBF containing water, the above acetonitrile reaction mass was added drop wise with stifling. The solid was filtered and washed with water. The solid was dried in air oven at 45-50C. Dry Wt. 4.5 gm. HPLC purity 99.23%.
  • 41
  • [ 1256388-51-8 ]
  • C49H54N8O7 [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.2 g With trifluoroacetic acid; at 65 - 70℃; for 48h; The compound of formula I (1.5g) and Trifluoroacetic acid (iSniL) were stifled and heated to 65-70C and maintained for 48h.The reaction mixture was distilled under vacuum at 50-60C. Ethyl acetate (2OniL) and water (2OmL) were charged to the above reaction mixture followed by stifling and basifying with aqueous ammonia (7mL). Theethyl acetate layer was washed with water and brine solution and distilled under vacuum at 45-50C. Wt - 1.2g HPLC purity - 96.83%.?H NMR (300MHz), (DMSO-d6): 8.007-7.844 (6.7H), 7.573-6.950 (4.49H), 5.203 (1H), 4.607 (1H), 4.55 (1H), 4.167-4.002 (2H), 3.77 (2.2H), 3.36 (6.8H), 2.65 (1H), 2.4-1.221 (12H), 0.98-0.576 (14H).
  • 42
  • [ 1256388-51-8 ]
  • ledipasvir phosphate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With phosphoric acid; In ethyl acetate; General procedure: To lOg of Ledipasvir in 50mL of ethyl acetate; 4.2g of p-toluene sulfonic acid was added and the reaction mixture was stirred. The generated solid was isolated byfiltration and washed with ethyl acetate to obtain 10.5g of ditosylate salt of ledipasvir?
  • 43
  • [ 1256388-51-8 ]
  • ledipasvir hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; In 1,4-dioxane; ethyl acetate; General procedure: To lOg of Ledipasvir in 50mL of ethyl acetate; 4.2g of p-toluene sulfonic acid was added and the reaction mixture was stirred. The generated solid was isolated byfiltration and washed with ethyl acetate to obtain 10.5g of ditosylate salt of ledipasvir.
  • 44
  • [ 1256388-51-8 ]
  • [ 3144-16-9 ]
  • ledipasvir camphor sulfonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In isopropyl alcohol; General procedure: To lOg of Ledipasvir in 50mL of ethyl acetate; 4.2g of p-toluene sulfonic acid was added and the reaction mixture was stirred. The generated solid was isolated byfiltration and washed with ethyl acetate to obtain 10.5g of ditosylate salt of ledipasvir?
  • 45
  • ledipasvir phosphate [ No CAS ]
  • [ 1256388-51-8 ]
YieldReaction ConditionsOperation in experiment
With ammonium hydroxide; In water; at 10 - 20℃;pH 9 - 9.5; Ledipasvir phosphate (50g) and distilled water (1000 ml) were mixed, the reactionmixture was cooled to 10-20C and basified with aqueous ammonia solution to pH9.0-9.5. The reaction mixture was stirred and extracted with methylene dichloride at20-30C. The separated methylene dichloride layer was washed with distilled water to obtain solid residue. To the solid residue obtained was added ethyl acetate and heated to 40-50C to get clear solution and cooled to 25-30C. Acetone was added tothe above clear solution and heated to 40-50C for 15-20 mm. Thereafter reaction mass was cooled to 20-25C and maintained for 12h. The solid precipitates were filtered and washed with acetone and dried under vacuum. The solid wet cake obtained was added to acetonitrile, stined and reaction mass was heated to 40-50 to get clear solution. This clear acetonitrile solution was added drop wise into distilledwater at 20-30C. The reaction mass was stirred for 3-4 h, filtered and washed with distilled water and dried in vacuum oven at 50-55C for 12h to get the Ledipasvir Amorphous Form. HPLC purity: > 99.5%.
  • 46
  • methyl (1-(6-(4-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-yl)carbamate [ No CAS ]
  • [ 1256388-51-8 ]
  • 47
  • C47H51F2N7O5*(x)H3O4P [ No CAS ]
  • [ 1256388-51-8 ]
  • 48
  • (x)C4H6O4*C47H51F2N7O5 [ No CAS ]
  • [ 1256388-51-8 ]
  • 49
  • C42H43F2N7O3*(x)ClH [ No CAS ]
  • [ 1256388-51-8 ]
  • 50
  • [ 1296797-09-5 ]
  • [ 1256388-51-8 ]
  • 51
  • [ 1256388-50-7 ]
  • [ 1378387-87-1 ]
  • [ 1256388-51-8 ]
YieldReaction ConditionsOperation in experiment
90% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In tert-Amyl alcohol; water; at 90℃; for 16h;Inert atmosphere; Compound 13-Br (3.4 g, 5.675 mmol), compound 14-B (3.1 g, 6.243 mmol), PdCl2(dppf) (0.141 g, 0.2838 mmol), potassium carbonate (2.353 g, 17.025 mmol), water (10 mL) and tert-amyl alcohol (50 mL) were added into a three-necked bottle. Under nitrogen the mixture was heated to 90 C. and stirred for 16 hours. After that the mixture was cooled to room temperature and ethyl acetate (100 mL) was added. The mixture was washed with brine (200 mL) twice. The organic phase was dried over anhydrous sodium sulfate and the solvent was distilled off to give the product (4.54 g, yield 90%), in which the content of compound 1-LDV is 99.3% and the content of defluorinated impurity is 0.13% (220 nm).
  • 52
  • C42H43F2N7O3*(x)ClH [ No CAS ]
  • [ 111398-44-8 ]
  • [ 1256388-51-8 ]
YieldReaction ConditionsOperation in experiment
90% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; Compound 9 hydrochloride (4.2 g, 5 mmol), (S)-2-methoxycarbonylamino-3-methyl-butyric acid (0.963 g, 5.5 mmol), EDCI (1.437 g, 7.5 mmol), HOBt (1.013 g, 7.5 mmol), triethylamine (2.53 g, 25 mmol) and DMF (100 mL) were added into a three-necked bottle. The mixture was stirred at 20 C. for 16 hours. After that ethyl acetate (100 mL) was added and the mixture was washed with brine (200 mL) twice. The organic phase was dried over anhydrous sodium sulfate and the solvent was distilled off to give the product (4.0 g, yield 90%) in which the content of compound 1-LDV is 99% and the content of defluorinated impurity is 0.15% (220 nm).
  • 53
  • C59H70F2N8O10 [ No CAS ]
  • [ 1256388-51-8 ]
YieldReaction ConditionsOperation in experiment
100% With hydrogenchloride; In 1,4-dioxane; dichloromethane; at 10℃; for 5h; To a three-necked flask compound 1?-LDV-Boc-Boc (5.45 g, 5 mmol) and DCM (40 mL) were added, to which a solution of HCl in dioxane (4 M/L, 40 mL) was added dropwise with stirring at 10 C. After the addition the mixture was stirred for 5 hours. Then the solvent was distilled off to give the product (4.44 g, yield 100%).
  • 54
  • C63H60Cl2F2N8O8 [ No CAS ]
  • [ 1256388-51-8 ]
YieldReaction ConditionsOperation in experiment
100% With potassium phosphate; In tert-Amyl alcohol; water; at 90℃; for 5h; Compound 1?-LDV-Bz-Bz (5.25 g, 4.5 mmol), potassium phosphate aqueous solution (1M/L, 50 mL) and tert-amyl alcohol (50 mL) were added to a three-necked flask, and the temperature was raised to 90 C. The mixture was stirred for 5 hours, then cooled to room temperature and extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to give the product (4 g, yield 100%).
  • 55
  • C2H2O4*C45H48F2N6O4 [ No CAS ]
  • [ 1256388-51-8 ]
  • 56
  • C35H32F2N6*4ClH [ No CAS ]
  • [ 74761-41-4 ]
  • [ 1256388-51-8 ]
YieldReaction ConditionsOperation in experiment
Preparation steps: 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-hydroxybenzotriazole, N-(methoxycarbonyl)-L-proline and N,N-dimethylformamide were added to the reaction kettle, the reaction mixture was stirred at 20 C for 0.5 hours, and the solution was then cooled to 0 C. LD-P and N-methylmorpholine were added to the reactor, naturally warmed to room temperature, and stirring was continued for 3.5 hours. Ethyl acetate and water were added, the layers were separated, and the organic phase was washed with 4% sodium hydrogen carbonate and water, and then The organic layer was distilled to 2 volumes, cooled to 20 C, acetone was added to the reactor, stirring was continued for 2.5 hours, and the mixture was centrifuged. The filter cake was washed with acetone and dried to obtain a solid LD-Q.
  • 57
  • [ 84348-38-9 ]
  • [ 1256388-51-8 ]
  • 58
  • [ 1412903-77-5 ]
  • [ 1256388-51-8 ]
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