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Chemical Structure| 1009119-83-8
Chemical Structure| 1009119-83-8
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Product Details of [ 1009119-83-8 ]

CAS No. :1009119-83-8 MDL No. :MFCD28404675
Formula : C26H32Cl4N6 Boiling Point : -
Linear Structure Formula :- InChI Key :AYOXSBJGFNPGNK-VDUNKYASSA-N
M.W : 570.38 Pubchem ID :91864750
Synonyms :

Calculated chemistry of [ 1009119-83-8 ]

Physicochemical Properties

Num. heavy atoms : 36
Num. arom. heavy atoms : 22
Fraction Csp3 : 0.31
Num. rotatable bonds : 5
Num. H-bond acceptors : 4.0
Num. H-bond donors : 4.0
Molar Refractivity : 162.88
TPSA : 81.42 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -5.37 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 6.21
Log Po/w (WLOGP) : 6.78
Log Po/w (MLOGP) : 2.59
Log Po/w (SILICOS-IT) : 5.4
Consensus Log Po/w : 4.2

Druglikeness

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

Water Solubility

Log S (ESOL) : -7.41
Solubility : 0.0000221 mg/ml ; 0.0000000388 mol/l
Class : Poorly soluble
Log S (Ali) : -7.71
Solubility : 0.0000112 mg/ml ; 0.0000000197 mol/l
Class : Poorly soluble
Log S (SILICOS-IT) : -9.38
Solubility : 0.000000236 mg/ml ; 0.0000000004 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 4.52

Safety of [ 1009119-83-8 ]

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 [ 1009119-83-8 ]

* 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 [ 1009119-83-8 ]

[ 1009119-83-8 ] Synthesis Path-Downstream   1~3

  • 1
  • [ 1009119-83-8 ]
  • [ 1009119-65-6 ]
YieldReaction ConditionsOperation in experiment
77% Stage #1: N-methoxycarbonyl-L-valine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetonitrile at 20℃; for 1h; Stage #2: methyl N-[(2S)-1-[(2S)-2-[5-[4-[4-[2-[(2S)-1-[(2S)-2-(methoxycarbonylamino)-3-methylbutanoyl]pyrrolidin-2-yl]-1H-imidazol-5-yl]phenyl]phenyl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate hydrochloride With N-ethyl-N,N-diisopropylamine In acetonitrile at 0 - 20℃; for 22.75h; Stage #3: With hydrogenchloride; sodium chloride more than 3 stages; 24.23 A 50 mL flask equipped with a stir bar was sequentially charged with 2.5 mL acetonitrile, 0.344 g (2.25 mmol, 2.5 equiv) hydroxy benzotriazole hydrate, 0.374 g (2.13 mmol, 2.4 equiv) N-(methoxycarbonyl)-L-valine, 0.400 g (2.09 mmol, 2.4 equiv) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and an additional 2.5 mL acetonitrile. The resulting solution was agitated at 20° C. for 1 hour and charged with 0.501 g (0.88 mmol, 1 equiv) Example A-1e-4. The slurry was cooled to about 0° C. and 0.45 g (3.48 mmol, 4 equiv) diisopropylethylamine was added over 30 minutes while maintaining a temperature below 10° C. The solution was slowly heated to 15° C. over 3 hours and held at 15° C. for 16 hours. The temperature was increased to 20° C. and stirred for 3.25 hours. The resulting solution was charged with 3.3 g of 13 wt % aqueous NaCl and heated to 50° C. for 1 hour. After cooling to 20° C., 2.5 mL of isopropyl acetate was added. The rich organic phase was washed with 2×6.9 g of a 0.5 N NaOH solution containing 13 wt % NaCl followed by 3.3 g of 13 wt % aqueous NaCl. The mixture was then solvent exchanged into isopropyl acetate by vacuum distillation to a target volume of 10 mL. The resulting hazy solution was cooled to 20° C. and filtered through a 0.45 μm filter. The clear solution was then solvent exchanged into ethanol by vacuum distillation with a target volume of 3 mL. 1.67 mL (2.02 mmol, 2.3 equiv) of 1.21 M HCl in ethanol was added. The mixture was then stirred at 25° C. for 15 hours. The resulting slurry was filtered and the wet cake was washed with 2.5 mL of 2:1 acetone:ethanol. The solids were dried in a vacuum oven at 50° C. to give 0.550 g (0.68 mmol, 77%) of the desired product.Recrystallization of Example 24-23A solution of Example 24-23 prepared above was prepared by dissolving 0.520 g of the above product in 3.65 mL methanol. The solution was then charged with 0.078 g of type 3 Cuno Zeta loose carbon and allowed to stir for 0.25 hours. The mixture was then filtered and washed with 6 ml of methanol. The product rich solution was concentrated down to 2.6 mL by vacuum distillation. 7.8 mL acetone was added and allowed to stir at 25° C. for 15 h. The solids were filtered, washed with 2.5 mL 2:1 acetone:ethanol and dried in a vacuum oven at 70° C. to give 0.406 g (57.0%) of the desired product as white crystals: 1H NMR (400 MHz, DMSO-d6, 80° C.): 8.02 (d, J=8.34 Hz, 4H), 7.97 (s, 2H), 7.86 (d, J=8.34 Hz, 4H), 6.75 (s, 2H), 5.27 (t, J=6.44 Hz, 2H), 4.17 (t, J=6.95 Hz, 2H), 3.97-4.11 (m, 2H), 3.74-3.90 (m, 2H), 3.57 (s, 6H), 2.32-2.46 (m, 2H), 2.09-2.31 (m, 6H), 1.91-2.07 (m, 2H), 0.88 (d, J=6.57 Hz, 6H), 0.79 (d, J=6.32 Hz, 6H); 13C NMR (75 MHz, DMSO-d6): δ 170.9, 156.9, 149.3, 139.1, 131.7, 127.1, 126.5, 125.9, 115.0, 57.9, 52.8, 51.5, 47.2, 31.1, 28.9, 24.9, 19.6, 17.7; IR (neat, cm-1): 3385, 2971, 2873, 2669, 1731, 1650. Anal. Calcd for C40H52N8O6Cl2: C, 59.18; H, 6.45; N, 13.80; Cl, 8.73. Found C, 59.98; H, 6.80; N, 13.68; Cl, 8.77. mp 267° C. (decomposed). Characteristic diffraction peak positions (degrees 2θ+/-0.1) (at) RT, based on a high quality pattern collected with a diffractometer (CuKα) with a spinning capillary with 2θ calibrated with a NIST other suitable standard are as follows: 10.3, 12.4, 12.8, 13.3, 13.6, 15.5, 20.3, 21.2, 22.4, 22.7, 23.7.
Multi-step reaction with 2 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; 4-methyl-morpholine / N,N-dimethyl-formamide / 1 h / -10 - 35 °C 1.2: 6 h / -5 - 35 °C 2.1: hydrogenchloride / isopropyl alcohol; ethanol / 18 h / 25 - 40 °C
  • 2
  • [ 1009119-83-8 ]
  • [ 74761-42-5 ]
  • [ 1009119-65-6 ]
YieldReaction ConditionsOperation in experiment
76.3% Stage #1: N-methoxycarbonyl-L-valine With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetonitrile at 20℃; for 1h; Stage #2: methyl N-[(2S)-1-[(2S)-2-[5-[4-[4-[2-[(2S)-1-[(2S)-2-(methoxycarbonylamino)-3-methylbutanoyl]pyrrolidin-2-yl]-1H-imidazol-5-yl]phenyl]phenyl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate hydrochloride With N-ethyl-N,N-diisopropylamine In acetonitrile at 0 - 15℃; for 15.5h; Stage #3: With hydrogenchloride In ethanol at 20 - 50℃; for 26h; Preparation of Compound (I); A 1 L jacketed flask equipped with a nitrogen line and an overhead stirrer was sequentially charged with 100 mL acetonitrile, 13.69 g (89.4 mmol, 2.5 equiv) hydroxybenzotriazole hydrate, 15.07 g (86 mmol, 2.4 equiv) N-(methoxycarbonyl)-L-valine, 16.46 g (85.9 mmol, 2.4 equiv) 1-(3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride and an additional 100 mL acetonitrile. The resulting solution was agitated at 20° C. for 1 hour and charged with 20.4 g (35.8 mmol, 1 equiv) of purified Compound 7. The slurry was cooled to about 0° C. and 18.47 g (142.9 mmol, 4 equiv) diisopropylethylamine was added over 30 minutes while maintaining a temperature below 10° C. The solution was slowly heated to 15° C. over 3 hours and held at 15° C. for 12 hours. The resulting solution was charged with 120 mL 13 wt % aqueous NaCl and heated to 50° C. for 1 hour. After cooling to 20° C., 100 mL of isopropyl acetate was added. The biphasic solution was filtered through a 0.45 μm filter and the mixture split. The rich organic phase was washed with 2×240 mL of a 0.5 N NaOH solution containing 13 wt % NaCl followed by 120 mL 13 wt % aqueous NaCl. The mixture was then solvent exchanged into isopropyl acetate by vacuum distillation with a target volume of 400 mL. The resulting hazy solution was cooled to 20° C. and filtered through a 0.45 μm filter. The clear solution was then solvent exchanged into ethanol by vacuum distillation with a target volume of 140 mL. While maintaining a temperature of 50° C., 66.4 mL (82.3 mmol, 2.3 equiv) of 1.24M HCl in ethanol was added. The mixture was then charged with 33 mg (0.04 mmol, 0.001 equiv) of seed crystals of Compound (I) (see preparation below) and the resulting slurry was stirred at 50° C. for 3 hours. The mixture was cooled to 20° C. over 1 hour and aged at that temperature for an additional 22 hours. The slurry was filtered and the wet cake was washed with 100 mL of 2:1 acetone:ethanol. The solids were dried in a vacuum oven at 70° C. to give 22.15 g (27.3 mmol, 76.3%) of the desired product.
76.3% Stage #1: N-methoxycarbonyl-L-valine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetonitrile at 20℃; for 1h; Stage #2: methyl N-[(2S)-1-[(2S)-2-[5-[4-[4-[2-[(2S)-1-[(2S)-2-(methoxycarbonylamino)-3-methylbutanoyl]pyrrolidin-2-yl]-1H-imidazol-5-yl]phenyl]phenyl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate hydrochloride With N-ethyl-N,N-diisopropylamine In acetonitrile at 15℃; for 12h; 1 MOC-L- valine 15.07g, 1-hydroxybenzotriazole 13.69g, 1 ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride 16.46g was dissolved in 200mL acetonitrile, stirred at 20 degrees for one hour. Was then added to the reaction system 20.4g methyl N-[(2S)-1-[(2S)-2-[5-[4-[4-[2-[(2S)-1-[(2S)-2-(methoxycarbonylamino)-3-methylbutanoyl]pyrrolidin-2-yl]-1H-imidazol-5-yl]phenyl]phenyl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate hydrochloride and N,N-diisopropylethylamine 18.47g, stirred for 12 hours at 15 degrees. After completion of the reaction it was washed with 0.5N sodium hydroxide solution and 13% 120mL brine twice. The organic phase was poured into isopropyl acetate solution, was concentrated and filtered. The filtrate was added ethanol and concentrated to 140mL. Was added at 50 degrees 1.24M HCl in ethanol 66.4mL. After addition of seed crystals, followed by stirring at 50 degrees for 3 hours, cooled to room temperature and stirred for 22 hours. Filtered, the filter cake with 2: 1 solution of ethanol, washed with acetone, the solid was dried at 70 deg. C to give 22.15g of product, yield 76.3%, overall yield was 31%.
76.1% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In acetonitrile at 0 - 15℃; for 18h; Synthesis of daclatasvir hydrochloride (6.78, 11.7 mmol), HBOT 3.88, 28.1 mmol), EDCl (5.48, 28.1 mmol) and acetonitrile(50 mL) were added into the reaction flask, cooled to about 0 ° C and DIPEA (6 g, 46.8 mmol) was added dropwise; Heated to 15 ° C, reacted for 18 hours, concentrated to 20 mL under reduced pressure, washed three times with ethyl acetate (55 mL), saturated sodium chloride (22 mL). then filtered was carry out and the filtrate was concentrated to dryness. Ethanol (22 mL) was added, the temperature was raised to 50 ° C, 2M of HCl ethanol solution (5.5 mL) was added dropwise and incubated for 3 hours. Cooled to 20 ° C, stirred for 3 hours, filtered to give Khaki color (earthy soil color) Daclatasvir crude; The crude product of Daclatasvir was dissolved in methanol (33 mL) and the activated charcoal (0.6 g) and was incubated at 50 ° C for 3 hours. The filter was washed with 16 mL of methanol, the filtrate was concentrated to 8 mL, heated to 50 ° C, acetone (11mL) was added and incubated for 3 hours; ] Cooled to 25 ° C then stirred for 2 hours and filteration was carried out . Filter cake was washed with 10 mL of the solution (ethanol: acetone = 1: 1) and dried to give Daclatasvir, an off-white solid (7.2 g, yield 76.1%).
74% Stage #1: N-methoxycarbonyl-L-valine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetonitrile at 20℃; for 1h; Stage #2: methyl N-[(2S)-1-[(2S)-2-[5-[4-[4-[2-[(2S)-1-[(2S)-2-(methoxycarbonylamino)-3-methylbutanoyl]pyrrolidin-2-yl]-1H-imidazol-5-yl]phenyl]phenyl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate hydrochloride With N-ethyl-N,N-diisopropylamine In acetonitrile at 5 - 20℃; for 17h; Stage #3: With hydrogenchloride In ethanol at 20 - 50℃; for 6h; Alternative Preparation of Compound (I); A jacketed reactor equipped with a mechanical agitator, a thermocouple and a nitrogen inlet was sequentially charged with 10 L acetonitrile, 0.671 kg (4.38 moles, 2.50 equiv) 1-hydroxybenzotriazole, 0.737 kg (4.21 moles, 2.40 equiv) N-(methoxycarbonyl)-L-valine and 0.790 kg (4.12 moles, 2.35 equiv) 1-(3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride. The mixture was agitated at 20° C. for 1 hour, cooled to 5° C. and charged with 1 kg (1.75 moles, 1.00 equiv) Compound 7. While maintaining a temperature <10° C., 0.906 kg (7.01 moles, 4 equiv) diisopropylethylamine was added. The mixture was heated to 15-20° C. over 2 hours and agitated for an additional 15 hours. After the reaction was complete, the mixture was washed once with 6.0 L 13 wt % aqueous NaCl, twice with 6.1 L (6.12 moles, 3.5 equiv) 1.0 M aqueous NaOH containing 13 wt % NaCl and once with 6.0 L 13 wt % aqueous NaCl. Water was then removed from the rich organic solution via azeotropic distillation. The mixture was cooled to 20° C., agitated for 1 hour and filtered. The rich organic solution was then solvent exchanged into EtOH via vacuum distillation to a target volume of 5 L. While maintaining a temperature of 50° C., 3.2 L (4.0 moles, 2.3 equiv) 1.25M HCl in EtOH was charged. The mixture was seeded with 1.6 g Compound (I) (see preparation below) and agitated at 50° C. for 3 hours. The resulting slurry was cooled to 20° C. and agitated for at least 3 hours. The product was collected by filtration and washed with 5 L 2:1 acetone:EtOH to give 1.29 kg (ca. 90 wt % product) of wet crude product. A reactor equipped with an overhead agitator, nitrogen inlet and thermocouple was charged with 1.11 kg of the above crude product and 7 L methanol. The resulting solution was treated with Cuno Zeta Carbon 55SP. The carbon was washed with 15 L MeOH and the combined filtrate and wash was concentrated down to 4 L via vacuum distillation. The concentrated solution was charged with 5 L acetone and seeded with 1.6 g Compound (I) (see preparation below) while maintaining a temperature of 50° C. An additional 10 L acetone was charged and the resulting slurry was stirred at 50° C. for 3 hours. The slurry was cooled to 20° C. and allowed to agitate at 20° C. for 3 hours. The product was collected by filtration, washed with 5 L 2:1 acetone:EtOH and dried under vacuum at 50-60° C. to give 0.900 kg (1.11 moles, 74% adjusted) of Compound (I).
Stage #1: methyl N-[(2S)-1-[(2S)-2-[5-[4-[4-[2-[(2S)-1-[(2S)-2-(methoxycarbonylamino)-3-methylbutanoyl]pyrrolidin-2-yl]-1H-imidazol-5-yl]phenyl]phenyl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate hydrochloride; N-methoxycarbonyl-L-valine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In acetonitrile at 24 - 30℃; for 18h; Stage #2: With hydrogenchloride In ethanol; tert-butyl methyl ether; isopropyl alcohol at 20 - 50℃; for 12h; Preparation of Seed Crystals of Compound (I); A 250 mL round-bottom flask was charged with 6.0 g (10.5 mmol, 1 equiv) Compound 5, 3.87 g (22.1 mmol, 2.1 equiv) N-(methoxycarbonyl)-L-valine, 4.45 g (23.2 mmol, 2.2 equiv) 1-(3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.289 g (2.14 mmol, 0.2 equiv) 1-hydroxybenzotriazole, and 30 mL acetonitrile. The resulting slurry was then charged with 7.33 mL (42.03 mmol, 4 equiv) diisopropylethylamine and allowed to stir at 24-30° C. for about 18 hours. The mixture was charged with 6 mL of water and heated to 50° C. for about 5 hours. The mixture was cooled and charged with 32 mL ethyl acetate and 30 mL water. The layers were separated and the rich organic layer was washed with 30 mL of 10 wt % aqueous NaHCO3, 30 mL water, and 20 mL of 10 wt % aqueous NaCl. The rich organic layer was then dried over MgSO4, filtered, and concentrated down to a residue. The crude material was then purified via flash chromatography (silica gel, 0-10% methanol in dichloromethane) to provide the free base of Compound (I).The free-base of Compound (I) (0.03 g) was dissolved in 1 mL isopropanol at 20° C. Anhydrous HCl (70 μL, dissolved in ethanol, approximately 1.25M concentration) was added and the reaction mixture was stirred. To the solution was added methyl tert-butyl ether (1 mL) and the resulting slurry was stirred vigorously at 40° C. to 50° C. for 12 hours. The crystal slurry was cooled to 20° C. and filtered. The wet cake was air-dried at 20° C. A white crystalline solid (Form N-2 of Compound (I)) was obtained.
12 g Stage #1: N-methoxycarbonyl-L-valine With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetonitrile for 1h; Stage #2: methyl N-[(2S)-1-[(2S)-2-[5-[4-[4-[2-[(2S)-1-[(2S)-2-(methoxycarbonylamino)-3-methylbutanoyl]pyrrolidin-2-yl]-1H-imidazol-5-yl]phenyl]phenyl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate hydrochloride With N-ethyl-N,N-diisopropylamine In acetonitrile at 0 - 0.15℃; 6 EXAMPLE 6 Preparation of daclatasvir dihydrochioride To a stirred mixture of Moc-L-valine (7.5g) in acetonitrile (lOOmL) was added 1- hydroxy-7-azabenzotriazole (HOAt) (5. 84g) and 1 -ethyl-3 -(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1) (8. 2g) and the reaction mixture was stirred for about 1 h. 5,5 ‘-(4,4’-biphenyldiyl)bis(2-((28)-2-pyrrolidinyl)- 1H-imidazole) tetrahydrochloride (1 0.2g) was added. The reaction mixture was cooled to about 0°C to about 10°C and diisopropylethylamine (9.2g) was added to it. The reaction mixture was maintained at about 5°C to about 15°C for about 12h to about 16h. Water and ethyl acetate were added to the reaction mixture which was stirred for about 1 5mm. The two layers were separated and the aqueous layer was extracted with ethyl acetate.The combined organic layer was concentrated under vacuum and isopropyl alcohol was added to the obtained residue. The reaction mixture was concentrated till S volumes remain. Hydrochloric acid in isopropyl ether (1 Sg) was added to the reaction mixture which was stirred for about 12h to about 16h. The solid obtained was filtered, washed with isopropyl alcohol and dried under vacuum at about 45°C to about 55°C. Yield: 12g
Multi-step reaction with 2 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / acetonitrile / 0.1 h 1.2: 0 - 20 °C 1.3: 0.1 h / 40 - 45 °C 2.1: hydrogenchloride / water / pH 1-2
Ca. 94 %Chromat. With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 0.833333h; Flow reactor; 13 Synthesis of Daclatasvir Dihydrochloride of Formula I A solution of compound of formula 7 dissolved in DMF (0.017 M) was mixed with DIPEA (5.5 eq.) base and charged in one syringe. In another syringe solution of MOC-L-valine (0.057 M in DMF), EDC.HCl (2.5 equiv.), and HOBt (2.5 equiv.) were introduced into the capillary microreactor with a T-mixer using two separate syringe pumps. The two solutions were introduced to a T-mixer in a flow rate with the ratio of 1:3.3 (formula 7: Moc-L-valine) to maintain the stoichiometry, and then passed through a PTFE tubing (id=1000 μm, 1=12.8 m, vol.=10 ml) for the acid amine coupling during 50 min of residence time and 25° C. temperature (Table 7, entry 1). The resulting solution was charged with 30 mL cold water. After cooling to 20° C., 50 mL of ethyl acetate was added. The biphasic solution was filtered and the mixture split. The rich organic phase was washed with 2×40 mL sat (NaCl solution). The resulting hazy solution was cooled to 20° C. and filtered. The product was dried under vacuum at 50° C. to give 94% of LC-MS yield of formula I. Spectral data: 1H NMR (500 MHz, DMSO) δ 15.35 (s, 1H), 14.87 (s, 1H), 8.17 (s, 1H), 8.04 (d, J=7.9 Hz, 2H), 7.94 (d, J=7.9 Hz, 2H), 7.28 (d, J=8.2 Hz, 1H), 5.22 (t, J=6.6 Hz, 1H), 4.14 (t, J=7.5 Hz, 1H), 4.03 (d, J=6.4 Hz, 1H), 3.84 (s, 1H), 3.55 (s, 3H), 3.43 (d, J=31.9 Hz, 1H), 2.38 (d, J=6.1 Hz, 1H), 2.20 (s, 2H), 2.11 (dd, J=14.3, 7.8 Hz, 1H), 2.06-1.91 (m, 1H), 0.85 (d, J=6.6 Hz, 3H), 0.77 (d, J=6.6 Hz, 3H). 13C NMR (126 MHz, DMSO) δ 171.48 (s), 157.44 (s), 149.83 (s), 139.64 (s),132.20, 127.66 (s), 127.00, 126.35 (s), 115.53 (s), 58.38 (s), 53.33 (s), 52.02 (s), 47.68 (s), 31.54 (s), 29.45 (s), 25.39 (s), 20.05 (s), 18.23 (s). IR (νmax): 3379, 2963, 2827, 2655, 1724, 1642, 1524, 1434, 1355, 1312, 1240, 1197, 1101, 1024 cm-1 MS (EI): found: 738.39 (M+).

  • 3
  • [ CAS Unavailable ]
  • [ 74761-42-5 ]
  • [ 1009119-65-6 ]
YieldReaction ConditionsOperation in experiment
89% Stage #1: N-methoxycarbonyl-L-valine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetonitrile at 20℃; for 1h; Inert atmosphere; Stage #2: 1H-imidazole,5,5'-[1,1'-biphenyl]-4,4'-bis[2-(2S)-2-pyrrolidine-2yl hydrochloride] With N-ethyl-N,N-diisopropylamine In acetonitrile at 0 - 15℃; for 15.5h; Stage #3: With hydrogenchloride In ethanol at 50℃; 10 200 ml of acetonitrile and 27.38 g (178.8 mmol) were sequentially added to a 1-liter jacketed flask equipped with a nitrogen line and a stirrer.2.5 equivalents of hydroxybenzotriazole hydrate,30.14g (172mmol, 2.4 equivalents)N-(methoxycarbonyl)-L-proline,32.92g (171.8mmol, 2.4 equivalents)1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlorideAnd an additional 200 ml of acetonitrile.The resulting solution was stirred at 20 ° C for 1 h.Add 40.8 g (71.6 mmol, 1 equivalent) purified1H-imidazole, 5,5'-[1,1'-biphenyl]-4,4'-bis[2-(2S)-2-pyrrolidine hydrochloride](1:4).Cooling the slurry to about 0 ° C,36.94 g (285.8 mmol, 4 equivalents) of diisopropylethylamine were added over 30 min.At the same time keep the temperature below 10 °C.The solution was slowly heated to 15 ° C over 3 h and held at 15 ° C for 12 h. To the resulting solution was added 240 ml of a 13 wt% aqueous NaCl solution and heated to 50 ° C for 1 h.After cooling to 20 ° C, 200 ml of isopropyl acetate was added.The biphasic solution was filtered through a 0.45 um filter to separate the mixture.The organic phase was enriched with 2 x 480 ml of 0.5 N NaOH containing 13 wt% NaCl,The solution was washed and then washed with 240 ml of a 13 wt% aqueous NaCl solution.Then, the mixture was changed to isopropyl acetate by vacuum distillation to obtain a target volume of 800 ml.The resulting hazy solution was cooled to 20 ° C and filtered through a 0.45 um filter.Then, the transparent solution was changed to ethanol by vacuum distillation to obtain a target volume of 280 ml.132.8 ml (164.6 mmol, 2.3 eq.) of 1.24 M HCl in ethanol was added at a temperature maintained at 50 °C.Then, 66 mg (0.08 mol, 0.001 equivalent) of the compound (I) seed crystals were added to the mixture, and the resulting slurry was stirred at 50 ° C for 3 h. The mixture was cooled to 20 ° C in 1 h and re-cooked at this temperature for 22 h.The slurry was filtered and the wet cake was washed with 200 ml of 2:1 acetone:Wash with ethanol.The solid was dried in a vacuum oven at 70 ° C.44.8 g (54.6 mmol, 77.2%) of crude darafal hydrochloride was obtained.The chromatographic purity was 99.30%, the maximum single impurity was 0.41%, and the isomer was 0.37%.Dissolve 10 g of crude darafal hydrochloride in 69 ml of methanol.The solution was passed through a 47 mm Cuno Zeta Cabon 53 SP filter at ~5 psig at a flow rate of 58 ml/min.The carbon filter was rinsed with 101 ml of methanol.The solution was concentrated to 51 ml by vacuum distillation.Crystallization of 51 ml of acetone and 16 mg of dalataxel hydrochloride was carried out while maintaining the temperature at 40 to 50 ° C, and then, within 30 min,The resulting slurry was kept at 50 ° C for 2 h.Cool to 20 ° C in about 1 hour and hold at 20 ° C for 20 hours.Filtering the solid,Wash with 51 ml of 2:1 acetone:methanol,Dry in a vacuum box at 60 ° C,7g of purified dalataxel hydrochloride,The refined yield is 70%.The chromatographic purity is 99.40%,The largest single impurity was 0.18% and the isomer was 0.12%.
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