[ CAS No. 1009119-65-6 ] {[proInfo.proName]}

Name: 1009119-65-6|Methyl ((S)-1-((S)-2-(5-(4'-(2-((S)-1-((methoxycarbonyl)-L-valyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-[1,1'-biphenyl]-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate dihydrochloride|98+%
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Quality Control of [ 1009119-65-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 1009119-65-6 ]

CAS No. :	1009119-65-6	MDL No. :	MFCD25541736
Formula :	C₄₀H₅₂Cl₂N₈O₆	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BVZLLUDATICXCI-JMSCDMLISA-N
M.W :	811.80	Pubchem ID :	25154713
Synonyms :	BMS-790052 dihydrochloride;EBP 883 dihydrochloride;Daclatasvir dihydrochloride	Chemical Name :	Methyl ((S)-1-((S)-2-(5-(4'-(2-((S)-1-((methoxycarbonyl)-L-valyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-[1,1'-biphenyl]-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate dihydrochloride

Calculated chemistry of [ 1009119-65-6 ]

Physicochemical Properties

Num. heavy atoms :	56
Num. arom. heavy atoms :	22
Fraction Csp3 :	0.45
Num. rotatable bonds :	17
Num. H-bond acceptors :	8.0
Num. H-bond donors :	4.0
Molar Refractivity :	225.79
TPSA :	174.64 Å²

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) :	-6.5 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	6.69
Log Po/w (WLOGP) :	6.42
Log Po/w (MLOGP) :	1.56
Log Po/w (SILICOS-IT) :	5.22
Consensus Log Po/w :	3.98

Druglikeness

Lipinski :	2.0
Ghose :	None
Veber :	2.0
Egan :	2.0
Muegge :	4.0
Bioavailability Score :	0.17

Water Solubility

Log S (ESOL) :	-8.26
Solubility :	0.0000045 mg/ml ; 0.0000000055 mol/l
Class :	Poorly soluble
Log S (Ali) :	-10.16
Solubility :	0.0000000561 mg/ml ; 0.0000000001 mol/l
Class :	Insoluble
Log S (SILICOS-IT) :	-9.45
Solubility :	0.000000289 mg/ml ; 0.0000000004 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	3.0
Synthetic accessibility :	6.51

Safety of [ 1009119-65-6 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280	UN#:	N/A
Hazard Statements:	H302-H317	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1009119-65-6 ]

* 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 [ 1009119-65-6 ]

[ 1009119-65-6 ] Synthesis Path-Downstream 1~11

1
[ 1009119-83-8 ]
[ 1009119-65-6 ]

Yield	Reaction Conditions	Operation 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

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2008/50336, 2008, A1 Location in patent: Page/Page column 89-90
[2]Current Patent Assignee: VIATRIS INC - WO2016/178250, 2016, A1

2
[ 1009119-83-8 ]
[ 74761-42-5 ]
[ 1009119-65-6 ]

Yield	Reaction Conditions	Operation 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+).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2009/43107, 2009, A1 Location in patent: Page/Page column 9-10
[2]Current Patent Assignee: JIANGSU SULI FINE CHEMICAL - CN105753844, 2016, A Location in patent: Paragraph 0033; 0034
[3]Current Patent Assignee: SHANGHAI STEPUP PHARMACEUTICAL TECH - CN106432204, 2017, A Location in patent: Paragraph 0095-0101
[4]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2009/43107, 2009, A1 Location in patent: Page/Page column 10
[5]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2009/43107, 2009, A1 Location in patent: Page/Page column 11
[6]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2018/15847, 2018, A1 Location in patent: Paragraph 0128
[7]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2018/15847, 2018, A1
[8]Current Patent Assignee: COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH (IN) - US2020/346182, 2020, A1 Location in patent: Paragraph 0174-0180

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[ 1009119-65-6 ]

Yield	Reaction Conditions	Operation in experiment
85.7%	With hydrogenchloride In methanol; water at 55℃;	1 Synthesis of daclatasvir In 1-4, 400 g of methanol and 20 g of 31% hydrochloric acid were added,The temperature was raised to 55 ° C to make it clear,Cooling to 20 crystallization 3h,Filtered to give crude,Add 400g of methanol and 5g of activated carbon heated to 55 and then filtered,The filtrate was concentrated to concentrate the original half,Cooling to 20 ,Crystallization 4h,After filtration, the solid was vacuum dried at 55 ° C to a moisture of less than 1.0%Get the final product daclatavir 111.9g,Purity 99.2%, yield 85.7%
	With hydrogenchloride In ethyl acetate at 20℃; for 1h;	2 Example 2 - Preparation of amorphous Form C of compound B Example 2 - Preparation of amorphous Form C of compound B MOC-L-Valine (8 g), HOBT Monohydrate (7 g) and EDC.HCI (8.8 g) were stirred in 125 mL of acetonitrile at 10-15°C under nitrogen for 1 hour. DCV Imidazole HCI (10 g) and Hunigs base (9.5 g) were added. The reaction mass was further stirred for 2-3 hours and 60 mL of isopropyl acetate was added. The organic layer was separated and washed with 60 mL of 13 wt% aqueous NaCI solution, 2 x120 mL of 0.5 N NaOH solution containing 13 wt % aqueous NaCI solution followed by 60 mL of 13 wt% aqueous NaCI solution. The organic layer was treated with charcoal (1.5 g) and silica gel (1.5 g) for 30 minutes at room temperature. The reaction mass was filtered on hyflo, washed with isopropyl acetate. The clear filtrate was distilled under reduced pressure to 2 volumes. A 15 mL solution of hydrochloric acid in ethyl acetate was added slowly. The reaction mass was cooled to room temperature and further stirred for 1 hour. The solid was isolated by filtration, washed with ethyl acetate and dried in a vacuum oven at 65°C for 24 hours to obtain amorphous Form C.
40 g	With hydrogenchloride In ethanol at 55℃; for 3h;	2 Weigh 48g compound N,N'-[[1,1'-biphenyl]-4,4'-diylbis[1H-imidazole-5,2-diyl-(2S)-2,1-pyrrolidinediyl[(1S)-1-(1-methylethyl)-2-oxo-2,1-ethanediyl]]]biscarbamic acid dimethyl ester into 500mL three-neck reaction flask, was added 300mL ethanol, completely dissolved at 55 deg. C then was added dropwise 19g 36% HCl in ethanol, maintaining the temperature and stirring was continued for 3 hours, allowed to cool overnight. Large amount of solid precipitated, was filtered, the filter cake washed with ethanol 2 times, and dried to obtain the final product N,N'-[[1,1'-biphenyl]-4,4'-diylbis[1H-imidazole-5,2-diyl-(2S)-2,1-pyrrolidinediyl[(1S)-1-(1-methylethyl)-2-oxo-2,1-ethanediyl]]]bis(carbamic acid) dimethyl ester dihydrochloride 40g, yield 86%, total yield 71%.

120 g	With hydrogenchloride In ethanol; isopropyl alcohol at 25 - 40℃; for 18h;	10 Example 10: Preparation of daclatasvir dihydrochloride The daclatasvir free base was taken in ethanol (480 mL) and added with HC1 in isopropyl alcohol (129.86 g) at about 40°C and stirred for about 6 hours. The resulting suspension was cooled to 25 - 35 °C and stirring continued for an additional 12 hours. The reaction mass was filtered and the solid was washed with ethanol (120 mL) to yield daclatasvir dihydrochloride as a solid. Yield: 120.0 g
	With hydrogenchloride In methanol at 25 - 55℃; for 4h;	6; 8 Preparation of daclatasvir dihydrochloride In 1 lit three necked round bottom flask equipped with mechanical stifler, thermometer, 124 g of amorphous form of daclatasvir free base and 150 ml methanol were taken at 25-35°C. Reaction mass was heated to 50-55°C. To the reaction mass slowly added 13% ethanolic HC1 (250 ml) at 50-55°C and stifled for 3 hr at same temperature. Reaction mass was allowed to cool to 25-30°C and stirred for 1 hr. The precipitated solid was filtered and washed with a mixture of methanol (33 ml) and ethanol (66 ml) and further dryed at 50-55°C to get daclatasvir dihydrochloride. Yield: 120 g. In 1 lit three necked round bottom flask equipped with mechanical stiner, thermometer, 100 g daclatasvir dihydrochloride and 500 ml methanol were taken at 25-30°C. The content was stined for 30 mm at 25-30°C. To this, 50 ml methanol slurry of 15 g PS-133 carbon was added and stined for 1 hr at 25-30°C.The content was filtered through hyflobed, and the bed was washed with 200 ml methanol. The filterate was concentrated partially under vacuum at 40-45°C till 300 ml methanol remains in the flask. Reaction mass was cooled to 25-30°C and 900 ml ethanol and 0.15 g seed material was added and stined for 12 hr at same temperature. The precipitated solid was filtered and washed with a mixture of methanol: ethanol (1:2; 100 ml) and further dried at 70-75°C under vacuumfor 12-15 hr to get pure daclatasvir dihydrochloride. Yield: 65 g; DSC: Fig. 3; PXRD:Fig. 4; Purity by HPLC: 99.8%; Formula A by HPLC: 0.02%; Formula C by HPLC:0.04%; Formula D by HPLC: Not detected (LOD-0.01%).
15.8 kg	With hydrogenchloride In ethanol at 25 - 45℃; for 14.5h; Large scale;	6 Synthesis and purification of crude dacarbazide In a reaction kettle, 18 kg of free base C was dissolved in 42 kg of ethanol and the temperature was raised to 45 ° C. And the reaction solution was keptA 2.2% solution of 20% hydrogen chloride in ethanol was slowly added to the above reaction solution at 45 ° C.And reacted at 45 ° C for 2.5 hours, the temperature of the reaction solution was lowered to 25 ° C and reacted at that temperature for 12 hours.The reaction solution was filtered and the filter cake was rinsed once with 5 kg of ethanol,Dried to give a pale yellow solid 15.8 kg,That is docetaxel crude product, the yield was 80.6%.The purity of crude dacarbavir was 98.5% by HPLC, and the content of single impurity in crude dacarbazepine was 0.2%.
	With hydrogenchloride In di-isopropyl ether; acetone	8.A EXAMPLE 8 Preparation of amorphous daclatasvir dihydrochioride (A) To a stirred mixture of daclatasvir (2g) in acetone (3OmL) was added hydrochloricacid in isopropyl ether (1 .6g). The reaction mixture was stirred for about 2h to about 3h.The precipitated solid was filtered under nitrogen, washed with acetone and dried under vacuum at about 40°C to about 45°C.
1.6 g	With hydrogenchloride In water; acetone at 25 - 30℃; for 3h;	12 Example-12: Preparation of crystalline Form-M of dimethyl ((2S,2'S)-((2S,2'S)-2,2'-(5,5'-([1,1'-biphenyl]-4,4'-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate, hydrochloride (1:2) Acetone (20 ml) added to Daclatasvir (2 gr) at 25-30°C and stirred for 10 min. at same temperature. Acidify the above obtained clear solution with aqueous HC1 (0.8 ml) at 25-30°C and stirred for 3 hours at same temperature. Filtered the precipitated solid and washed with methylene chloride followed by dried under vacuum to get the title compound. (Yield: 1.6 gr). The PXRD pattern of the title compound was similar to the PXRD pattern illustrated in figure-3.

Reference： [1]Current Patent Assignee: ANHUI YELLEN PHARMACEUTICAL - CN107501243, 2017, A Location in patent: Paragraph 0021
[2]Current Patent Assignee: CIPLA LTD - WO2016/102979, 2016, A1 Location in patent: Page/Page column 27
[3]Current Patent Assignee: JIANGSU SULI FINE CHEMICAL - CN105753844, 2016, A Location in patent: Paragraph 0044; 0045
[4]Current Patent Assignee: VIATRIS INC - WO2016/178250, 2016, A1 Location in patent: Page/Page column 26
[5]Current Patent Assignee: LAURUS LABS LIMITED - WO2017/21904, 2017, A1 Location in patent: Page/Page column 24; 25
[6]Current Patent Assignee: SICHUAN TONGSHENG BIOPHARMACEUTICAL - CN106256825, 2016, A Location in patent: Paragraph 0071-0073
[7]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2018/15847, 2018, A1 Location in patent: Paragraph 0130; 0131
[8]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2018/134842, 2018, A1 Location in patent: Page/Page column 36-37

4
[ 1007882-23-6 ]
methyl N-[(1S)-1-[(2S)-2-[5-[4-[4-[2-[(2S)-1-[(2S)-2-(methoxycarbonylamino)-3-methyl-butanoyl]pyrrolidin-2-yl]-1H-imidazol-5-yl]phenyl]phenyl]-1H-imidazol-2-yl]pyrrolidine-1-carbonyl]-2-methyl-propyl]carbamate dihydrochloride [ No CAS ]

Reference： [1]Patent: CN105753844,2016,A
[2]Patent: WO2016/178250,2016,A1
[3]Patent: WO2017/21904,2017,A1
[4]Patent: CN107501243,2017,A
[5]Patent: WO2018/15847,2018,A1
[6]Patent: WO2018/15847,2018,A1
[7]Patent: US2008/50336,2008,A1

5
[ 1895903-53-3 ]
[ 1009119-65-6 ]

Yield	Reaction Conditions	Operation in experiment
75.1%	With ammonium acetate In toluene at 90 - 100℃;	5 Embodiment 5,Dhaka his Wei synthesis of adds the ester (14) (33.7 g, 43mmol), ammonium acetate (35.1 g, 450mmol) and toluene (340 ml) to 500 ml bottle of the three-port, heating 90-100 degrees reaction 10-18 hours, after the reaction, cooling to 40-50 degrees, decompression concentrating to 130 ml left and right, and ethyl acetate (550 ml), with saturated sodium chloride (220 ml) washing three times, filtering, the filtrate concentrated to dry, adding ethanol (220 ml), heating up to 50 degrees, the 50 degrees, dropping 2M HCl ethanol solution of (55 ml), adds the seed crystal 30 mg, and in 50 degrees insulation 2-3 hours, cooling to 10-20 degrees, stirring 2-3 hours, filtering, obtain the dhaka he wei Cupin, adding methanol to the crude product (330 ml) dissolved, active carbon (6g), in 50 degrees insulation 1-3 hours, filtering, with 160 ml methanol washing, concentrating the filtrate to 65-85mL, reheated to 50 degrees, adds the acetone (110 ml), adds the seed crystal 30 mg, and in 50 degrees insulation 2-3 hours, cooling to 15-25 degrees stirring 1-2 hours, filtering, the filter cake is washed with ethanol: acetone = 1:1 solution 100 ml washing, drying to obtain dhaka he wei two hydrochloride, kind of white solid, (26.2g, yield 75.1%).
73%	Stage #1: C₄₀H₅₀N₄O₁₂ With ammonium acetate In toluene at 90 - 100℃; Stage #2: With hydrogenchloride In ethanol at 50℃;	5 Synthesis of Daclatasvir Into 500ml of three necked flask added esters(14)(31.2g,40mmol) prepared in Example 1-4, Ammonium acetate (30.8 g, 400 mmol) and toluene (300 mL). The reaction system is heated to 90 ~ 100 ° C and allowed to react for 10 ~ 18 hours. after the completion of the reaction, it was cooled to 40 ~ 50 ° C. The reaction system was concentrated under reduced pressure to about 120 mL, ethyl acetate (500 mL) was added and washed three times with saturated sodium chloride solution (200 mL), filtered, and the resulting filtrate was concentrated to dryness under reduced pressure. Add ethanol (200mL), raise the temperature to 50 ° C, and drop wise added HCl-ethanol solution (50mL) at a concentration of 2mol / L and at 50 ° C insulation for 2 ~ 3 hours. And then cooled to 10 ~ 20 ° C and then stirring the reaction for 2 ~ 3 hours. Filtration was carried out to obtain yellow Daclatasvir crude product. The crude Daclatasvir was added to methanol (300 mL), then add activated carbon (2g), at 50 ° C insulation was carried out for 1 ~ 2 hours. Filtration was carried then the resulting filtrate was concentrated under reduced pressure to 60 to 80 mL and heated to 50 ° C . Then add acetone (100 mL) and incubate at 50 ° C for 2 to 3 hours. Then cooled to 15 ~ 25 ° C, and then stirring for 1 ~ 2 hours. filtration, drying was carried out to obtain white solid Daclatasvir (23.7g), yield 73%.
59 g	Stage #1: C₄₀H₅₀N₄O₁₂ With ammonium acetate In toluene at 80℃; for 15h; Stage #2: With hydrogenchloride In ethanol for 2h;	2.3 Step three, synthesis of Daclatasvir To apply the above-mentioned intermediates 2 and ammonium acetate (160g, intermediate 2 and ammonium acetate in a molar ratio of 1:20) is dissolved in 400 ml in toluene, system temperature to 80 °C, stirring reaction 15h, after the reaction, cooling to room temperature, add in the system 200 ml and 400 ml water, stirring 30 min, hierarchical, sequentially an organic layer by washing with water, saturated salt water washing, drying by anhydrous sodium sulfate, added does thickly 200 ml ethanol, stirring, add 30 ml containing 0.3mol ethanol solution of hydrochloric acid, stirring 2h, filtered, the filter cake is washed with acetone washing, 74g white solid of crude, methanol/acetone recrystallization to obtain 59g white solid powder, step II and step three two-step total yield of 71%.

Reference： [1]Current Patent Assignee: SUZHOU BUYUE PHARMACEUTICAL - CN105622583, 2016, A Location in patent: Paragraph 0034; 0035; 0036
[2]Current Patent Assignee: SHANGHAI STEPOVRECHEM - CN105461701, 2016, A Location in patent: Paragraph 0045-0048
[3]Current Patent Assignee: ANHUI LIANCHUANG BIOLOGICAL MEDICINE - CN105777719, 2016, A Location in patent: Paragraph 0028; 0046; 0047; 0048

6
[ 15761-39-4 ]
[ 1009119-65-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 15 - 25 °C 1.2: 95 - 105 °C 2.1: hydrogenchloride / isopropyl alcohol; water / 0.5 - 0.55 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / acetonitrile / 1 h 3.2: 0 - 0.15 °C
	Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 15 - 25 °C 1.2: 95 - 105 °C 2.1: hydrogenchloride / isopropyl alcohol; water / 0.5 - 0.55 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / acetonitrile / 0.1 h 3.2: 0 - 20 °C 3.3: 0.1 h / 40 - 45 °C 4.1: hydrogenchloride / water / pH 1-2
	Multi-step reaction with 6 steps 1.1: N-ethyl-N,N-diisopropylamine / toluene / 4 h / 25 - 55 °C 2.1: toluene / 16 h / 25 - 95 °C 3.1: hydrogenchloride / isopropyl alcohol / 4 h / 25 - 65 °C 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / dichloromethane / 1.75 h / 0 - 20 °C 4.2: 14 h / 0 - 20 °C 5.1: potassium carbonate / 1,4-dioxane; water / 15 h / 25 - 85 °C 5.2: 4 h / 25 - 30 °C 6.1: sodium carbonate / dichloromethane; water / 0.25 h / 25 - 30 °C 6.2: 7 h / 0 - 30 °C

	Multi-step reaction with 6 steps 1.1: N-ethyl-N,N-diisopropylamine / toluene / 4 h / 25 - 55 °C 2.1: toluene / 16 h / 25 - 95 °C 3.1: hydrogenchloride / isopropyl alcohol / 4 h / 25 - 65 °C 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / dichloromethane / 1.75 h / 0 - 20 °C 4.2: 14 h / 0 - 20 °C 5.1: sodium phosphate dodecahydrate; tetrabutylammomium bromide; palladium 10% on activated carbon / methanol / 5 h / 25 - 70 °C / Inert atmosphere 5.2: 6 h / 5 - 10 °C 6.1: sodium carbonate / dichloromethane; water / 0.25 h / 25 - 30 °C 6.2: 7 h / 0 - 30 °C
	Multi-step reaction with 7 steps 1.1: N-ethyl-N,N-diisopropylamine / toluene / 4 h / 25 - 55 °C 2.1: toluene / 16 h / 25 - 95 °C 3.1: hydrogenchloride / isopropyl alcohol / 4 h / 25 - 65 °C 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / dichloromethane / 1.75 h / 0 - 20 °C 4.2: 14 h / 0 - 20 °C 5.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate / 1,4-dioxane / 15 h / 25 - 85 °C 6.1: potassium carbonate / 1,4-dioxane; water / 15 h / 25 - 85 °C 6.2: 4 h / 25 - 30 °C 7.1: sodium carbonate / dichloromethane; water / 0.25 h / 25 - 30 °C 7.2: 7 h / 0 - 30 °C
	Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 1.17 h / 20 °C 2.1: ammonium acetate / xylene / 2 h / 140 °C 3.1: sodium hydrogencarbonate / tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,2-dimethoxyethane; water / 5.75 h / 80 °C 4.1: hydrogenchloride / methanol / 23 h / 20 - 50 °C 5.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / acetonitrile / 1 h / 20 °C 5.2: 22.75 h / 0 - 20 °C
	Multi-step reaction with 6 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 1.17 h / 20 °C 2.1: ammonium acetate / xylene / 2 h / 140 °C 3.1: potassium acetate / tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,4-dioxane / 16.5 h / 80 °C 4.1: sodium hydrogencarbonate / tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,2-dimethoxyethane; water / 5.75 h / 80 °C 5.1: hydrogenchloride / methanol / 23 h / 20 - 50 °C 6.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / acetonitrile / 1 h / 20 °C 6.2: 22.75 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2018/15847, 2018, A1
[2]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2018/15847, 2018, A1
[3]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2018/134842, 2018, A1
[4]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2018/134842, 2018, A1
[5]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2018/134842, 2018, A1
[6]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2008/50336, 2008, A1
[7]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2008/50336, 2008, A1

7
[ 1802147-52-9 ]
[ 1009119-65-6 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride In water	12 EXAMPLE 12 Preparation of Daclatasvir dihydrochioride hydrate Moc-L-Valine 76. 8g was added into 1 000ml acetonitrile. The reaction mass was stirredand 59.2g HOBt and 80.7g of EDC.HC1 were added and the reaction mass stirred forabout 1 hour. The reaction mass was cooled to 15-20°C and bOg of compound obtained from example 11 was added. 90.6g of diisopropylethylamine was added to the reaction mass at 0-10°C. After complete addition, the reaction mass was maintained at 15-20°C. After completion of reaction, water and methylene dichloride were added. The reactionmass was stirred and aqueous and organic layers were separated. The aqueous layer was extracted with methylene dichloride and the combined organic layers were washed with sodium hydroxide solution and then once with 10% acetic acid solution and twice with 5% acetic acid solution followed by washing with sodium bicarbonate solution. The organic layer was distilled under vacuum and the residue dissolved in acetone andmethanol mixture. 54.7g of malonic acid was added to solution and heated to 40-45°C and stirred for about 1 hours. The reaction mass was cooled to 20-25°C and stirred for 12 hours. The malonate salt was filtered and washed with acetone. The wet cake was crystallized using acetone. The solid was filtered and washed with acetone (purity 99.75%). Wet cake was dissolved in water and ethyl acetate was added. The reactionmass was basified using aqueous ammonia solution, pH not less than 8.5. The aqueous and organic layers were separated. The organic layer was stirred with water and concentrated HC1 added till pH of aqueous layer was in between 1-2. Aqueous layer was separated and charcoaled. Solution filtered through hyflo and hyflo was washed with water. About 50 ml water was distilled from filtrate under vacuum and the reaction mass was heated to 50-55°C and stirred for 2-3 hours. The reaction mass was cooled to 20-30°C and then stirred for 12 hours. The solid obtained was filtered and washed with water and dried in air oven at 50-60°C. Isolated dry weight. 70.0g. Purity 99.86%.

Reference： [1]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2018/15847, 2018, A1 Location in patent: Paragraph 0134

8
[ 2234299-50-2 ]
[ 1009119-65-6 ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: dimethyl ((2S,2'S)-((2S,2'S)-2,2'-(5,5'-([1,1'-biphenyl]-4,4'-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate oxalic acid (1:2) With sodium carbonate In dichloromethane; water at 25 - 30℃; for 0.25h; Stage #2: With hydrogenchloride In dichloromethane; water at 0 - 30℃; for 7h;	13 Example-13: Preparation of pure crystalline Form-M of dimethyl ((2S,2'S)-((2S,2'S)-2,2'-(5,5'-([1,1'-biphenyl]-4,4'-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate, hydrochloride (1:2) Methylene chloride (2.25 lit), water (2.25 lit) were added to added to Daclatasvir oxalic acid (1 :2) (225 gms) at 25-30°C. Basified the above obtained reaction mixture with 5% aqueous Na2C03 solution at 25-30°C and stirred for 15 min at same temperature. Separated the both organic and aqueous layers. Extracted the aqueous layer with methylene chloride (2.25 lit). Combined the organic layers and washed with water. Passed the organic layer through 0.4 micron paper for particle free. Distilled off the solvent completely from the organic layer under reduced pressure. Dissolved the above obtained distillate in methylene chloride (1.8 lit) at 25-30°C and add aqueous HC1 (22 gms) at 0-10°C and stirred the reaction mixture for 15 min at same temperature. Slowly raised the reaction mixture temperature to 25- 30°C and stirred for 7 hrs at same temperature. Filtered the precipitated solid an washed with methylene chloride and then dried. Added acetone (1.8 lit) and methanol (2 ml) to the above obtained compound at 25-30°C and stirred for 90 min at same temperature. Filtered the solid, washed with acetone and then dried for 4-6 hours to get the title compound (Yield: 170 gms, 85%, purity by HPLC: 99.90%, water content: 1.17%), MR: 215-225°C).

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2018/134842, 2018, A1 Location in patent: Page/Page column 36; 37-38; 39; 40

9
[ 1007882-04-3 ]
[ 1009119-65-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: hydrogenchloride / isopropyl alcohol / 4 h / 25 - 65 °C 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / dichloromethane / 1.75 h / 0 - 20 °C 2.2: 14 h / 0 - 20 °C 3.1: potassium carbonate / 1,4-dioxane; water / 15 h / 25 - 85 °C 3.2: 4 h / 25 - 30 °C 4.1: sodium carbonate / dichloromethane; water / 0.25 h / 25 - 30 °C 4.2: 7 h / 0 - 30 °C
	Multi-step reaction with 4 steps 1.1: hydrogenchloride / isopropyl alcohol / 4 h / 25 - 65 °C 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / dichloromethane / 1.75 h / 0 - 20 °C 2.2: 14 h / 0 - 20 °C 3.1: sodium phosphate dodecahydrate; tetrabutylammomium bromide; palladium 10% on activated carbon / methanol / 5 h / 25 - 70 °C / Inert atmosphere 3.2: 6 h / 5 - 10 °C 4.1: sodium carbonate / dichloromethane; water / 0.25 h / 25 - 30 °C 4.2: 7 h / 0 - 30 °C
	Multi-step reaction with 5 steps 1.1: hydrogenchloride / isopropyl alcohol / 4 h / 25 - 65 °C 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / dichloromethane / 1.75 h / 0 - 20 °C 2.2: 14 h / 0 - 20 °C 3.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate / 1,4-dioxane / 15 h / 25 - 85 °C 4.1: potassium carbonate / 1,4-dioxane; water / 15 h / 25 - 85 °C 4.2: 4 h / 25 - 30 °C 5.1: sodium carbonate / dichloromethane; water / 0.25 h / 25 - 30 °C 5.2: 7 h / 0 - 30 °C

	Multi-step reaction with 3 steps 1.1: sodium hydrogencarbonate / tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,2-dimethoxyethane; water / 5.75 h / 80 °C 2.1: hydrogenchloride / methanol / 23 h / 20 - 50 °C 3.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / acetonitrile / 1 h / 20 °C 3.2: 22.75 h / 0 - 20 °C
	Multi-step reaction with 4 steps 1.1: potassium acetate / tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,4-dioxane / 16.5 h / 80 °C 2.1: sodium hydrogencarbonate / tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,2-dimethoxyethane; water / 5.75 h / 80 °C 3.1: hydrogenchloride / methanol / 23 h / 20 - 50 °C 4.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / acetonitrile / 1 h / 20 °C 4.2: 22.75 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2018/134842, 2018, A1
[2]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2018/134842, 2018, A1
[3]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2018/134842, 2018, A1
[4]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2008/50336, 2008, A1
[5]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2008/50336, 2008, A1

10
[ 1007881-98-2 ]
methyl N-[(1S)-1-[(2S)-2-[5-[4-[4-[2-[(2S)-1-[(2S)-2-(methoxycarbonylamino)-3-methyl-butanoyl]pyrrolidin-2-yl]-1H-imidazol-5-yl]phenyl]phenyl]-1H-imidazol-2-yl]pyrrolidine-1-carbonyl]-2-methyl-propyl]carbamate dihydrochloride [ No CAS ]

Reference： [1]Patent: US2008/50336,2008,A1
[2]Patent: US2008/50336,2008,A1

11
[ CAS Unavailable ]
[ 74761-42-5 ]
[ 1009119-65-6 ]

Yield	Reaction Conditions	Operation 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%.

Reference： [1]Current Patent Assignee: YANGTZE RIVER PHARMACEUTICAL GROUP CO LTD - CN109305962, 2019, A Location in patent: Paragraph 0048; 0049; 0050; 0051; 0053

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A358801[ 1009119-64-5 ]

Methyl ((S)-1-((S)-2-(5-(4'-(2-((S)-1-((methoxycarbonyl)-L-valyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-[1,1'-biphenyl]-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate

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Code	Phrase
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P321
P322
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P378
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Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
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H221	Flammable gas
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H261	In contact with water releases flammable gas
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Code	Phrase
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H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
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H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
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H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
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H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
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H332	Harmful if inhaled
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H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

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