[ CAS No. 1377049-84-7 ]

Name: 1377049-84-7|Methyl ((2S)-1-((2S,5S)-2-(9-(2-((2S,4S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate|99%
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SKU: A470907
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Quality Control of [ 1377049-84-7 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 1377049-84-7 ]

CAS No. :	1377049-84-7	MDL No. :	MFCD28411371
Formula :	C₄₉H₅₄N₈O₈	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	N/A
M.W :	883.00 g/mol	Pubchem ID :	67683363
Synonyms :	1. Velpatasvir

Calculated chemistry of of [ 1377049-84-7 ]

Physicochemical Properties

Num. heavy atoms :	65
Num. arom. heavy atoms :	30
Fraction Csp3 :	0.39
Num. rotatable bonds :	17
Num. H-bond acceptors :	10.0
Num. H-bond donors :	4.0
Molar Refractivity :	251.54
TPSA :	193.1 Å²

Pharmacokinetics

GI absorption :	Low
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-7.31 cm/s

Lipophilicity

Log Po/w (iLOGP) :	4.9
Log Po/w (XLOGP3) :	6.16
Log Po/w (WLOGP) :	5.84
Log Po/w (MLOGP) :	1.7
Log Po/w (SILICOS-IT) :	6.28
Consensus Log Po/w :	4.98

Druglikeness

Lipinski :	2.0
Ghose :	None
Veber :	2.0
Egan :	1.0
Muegge :	5.0
Bioavailability Score :	0.17

Water Solubility

Log S (ESOL) :	-8.41
Solubility :	0.0000034 mg/ml ; 0.0000000038 mol/l
Class :	Poorly soluble
Log S (Ali) :	-10.0
Solubility :	0.0000000886 mg/ml ; 0.0000000001 mol/l
Class :	Poorly soluble
Log S (SILICOS-IT) :	-12.21
Solubility :	0.0000000005 mg/ml ; 0.0 mol/l
Class :	Insoluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	3.0
Synthetic accessibility :	7.49

Safety of [ 1377049-84-7 ]

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 [ 1377049-84-7 ]

* 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 [ 1377049-84-7 ]

[ 1377049-84-7 ] Synthesis Path-Downstream 1~31

1
[ 1378391-39-9 ]
[ 1377049-84-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: pyridinium hydrobromide perbromide / dichloromethane; methanol / 1.75 h / 20 °C 2: caesium carbonate / 20 h / 50 °C 3: ammonium acetate / toluene; 2-methoxy-ethanol / 4.5 h / 110 °C 4: manganese(IV) oxide / dichloromethane / 13 h 5: hydrogenchloride / dichloromethane; 1,4-dioxane / 1 h / 20 °C 6: N-ethyl-N,N-diisopropylamine; 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate / N,N-dimethyl-formamide / 2 h / 20 °C
	Multi-step reaction with 5 steps 1.1: pyridinium hydrobromide perbromide / dichloromethane; methanol / 1.75 h / 20 °C 2.1: caesium carbonate / 2-methyltetrahydrofuran / 20 h / 50 °C 3.1: ammonium acetate / toluene; 2-methoxy-ethanol / 4.5 h / 110 °C 4.1: manganese(IV) oxide / dichloromethane / 13 h 5.1: hydrogenchloride / ethanol / 3 h / 50 °C 5.2: 2 h / 20 °C
	Multi-step reaction with 9 steps 1.1: hydrogenchloride / water; Isopropyl acetate / 60 - 65 °C / Industrial scale 2.1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / N,N-dimethyl-formamide / 20 - 25 °C / Industrial scale 3.1: ammonium acetate / toluene / 20 h / 80 - 100 °C / Inert atmosphere; Industrial scale 4.1: tribromopyridine / methanol; dichloromethane / 3 h / 10 - 15 °C / Industrial scale 5.1: potassium carbonate / N,N-dimethyl-formamide / 16 h / 20 - 40 °C / Inert atmosphere; Industrial scale 6.1: ammonium acetate / toluene / 20 h / 80 - 100 °C / Inert atmosphere; Industrial scale 7.1: manganese(IV) oxide / dichloromethane / 10 - 20 °C / Inert atmosphere; Industrial scale 7.2: 60 °C / Industrial scale 8.1: trifluorormethanesulfonic acid / methanol / 60 - 65 °C / Industrial scale 9.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / acetonitrile / 1 h / 10 - 15 °C / Industrial scale 9.2: 0 - 15 °C / Industrial scale

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2013/75029, 2013, A1
[2]Current Patent Assignee: GILEAD SCIENCES INC - US2013/309196, 2013, A1
[3]Current Patent Assignee: SHANGHAI BOCIMED PHARMACEUTICAL CO LTD - CN107573355, 2018, A

2
[ 1378391-42-4 ]
[ 1377049-84-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: caesium carbonate / 20 h / 50 °C 2: ammonium acetate / toluene; 2-methoxy-ethanol / 4.5 h / 110 °C 3: manganese(IV) oxide / dichloromethane / 13 h 4: hydrogenchloride / dichloromethane; 1,4-dioxane / 1 h / 20 °C 5: N-ethyl-N,N-diisopropylamine; 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate / N,N-dimethyl-formamide / 2 h / 20 °C
	Multi-step reaction with 4 steps 1.1: caesium carbonate / 2-methyltetrahydrofuran / 20 h / 50 °C 2.1: ammonium acetate / toluene; 2-methoxy-ethanol / 4.5 h / 110 °C 3.1: manganese(IV) oxide / dichloromethane / 13 h 4.1: hydrogenchloride / ethanol / 3 h / 50 °C 4.2: 2 h / 20 °C

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2013/75029, 2013, A1
[2]Current Patent Assignee: GILEAD SCIENCES INC - US2013/309196, 2013, A1

3
[ 1378391-43-5 ]
[ 1377049-84-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: ammonium acetate / toluene; 2-methoxy-ethanol / 4.5 h / 110 °C 2: manganese(IV) oxide / dichloromethane / 13 h 3: hydrogenchloride / dichloromethane; 1,4-dioxane / 1 h / 20 °C 4: N-ethyl-N,N-diisopropylamine; 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate / N,N-dimethyl-formamide / 2 h / 20 °C
	Multi-step reaction with 3 steps 1.1: ammonium acetate / toluene; 2-methoxy-ethanol / 4.5 h / 110 °C 2.1: manganese(IV) oxide / dichloromethane / 13 h 3.1: hydrogenchloride / ethanol / 3 h / 50 °C 3.2: 2 h / 20 °C
	Multi-step reaction with 4 steps 1: hydrogenchloride / ethanol; water / 0 - 80 °C 2: ammonium formate / 2-methoxy-ethanol / 100 - 105 °C 3: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 30 - 35 °C 4: acetic acid; 2,3-dicyano-5,6-dichloro-p-benzoquinone / tetrahydrofuran / 0 - 5 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2013/75029, 2013, A1
[2]Current Patent Assignee: GILEAD SCIENCES INC - US2013/309196, 2013, A1
[3]Current Patent Assignee: NANTONG CHANGYOU PHARMACEUTICAL TECH - CN110981879, 2020, A

4
[ 1378391-44-6 ]
[ 1377049-84-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: manganese(IV) oxide / dichloromethane / 13 h 2: hydrogenchloride / dichloromethane; 1,4-dioxane / 1 h / 20 °C 3: N-ethyl-N,N-diisopropylamine; 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate / N,N-dimethyl-formamide / 2 h / 20 °C
	Multi-step reaction with 2 steps 1.1: manganese(IV) oxide / dichloromethane / 13 h 2.1: hydrogenchloride / ethanol / 3 h / 50 °C 2.2: 2 h / 20 °C
	Multi-step reaction with 3 steps 1.1: manganese(IV) oxide / dichloromethane / 16 h / 20 °C 1.2: 4 h / 60 °C 2.1: ammonium hydroxide / dichloromethane; water / 0.17 h 3.1: 4-methyl-morpholine; 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride / dichloromethane / 16 h / 5 - 10 °C

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2013/75029, 2013, A1
[2]Current Patent Assignee: GILEAD SCIENCES INC - US2013/309196, 2013, A1
[3]Current Patent Assignee: SHANGHAI FOREFRONT PHARMCEUTICAL; SHANGHAI FOREFRONT PHARMACEUTICAL - CN106831737, 2017, A

5
[ 1378391-45-7 ]
[ 1377049-84-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: hydrogenchloride / dichloromethane; 1,4-dioxane / 1 h / 20 °C 2: N-ethyl-N,N-diisopropylamine; 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate / N,N-dimethyl-formamide / 2 h / 20 °C
	Multi-step reaction with 2 steps 1: hydrogenchloride / dichloromethane; 1,4-dioxane; methanol / 2 h 2: N-ethyl-N,N-diisopropylamine; 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate / N,N-dimethyl-formamide / 1 h
	Multi-step reaction with 2 steps 1: hydrogenchloride / dichloromethane; 1,4-dioxane; methanol / 2 h 2: 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2013/75029, 2013, A1
[2]Current Patent Assignee: BEIJING MEIBEITA PHARMACEUTICAL RES - CN107540679, 2018, A
[3]Current Patent Assignee: BEIJING MEIBEITA PHARMACEUTICAL RES - CN107556324, 2018, A

6
C₃₉H₄₅N₇O₅*(x)ClH [ No CAS ]
[ 50890-96-5 ]
[ 1377049-84-7 ]

Yield	Reaction Conditions	Operation in experiment
65 mg	With 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h;	PY Methyl {(2S)-l-[(2S,5S)-2-(9-{2-[(2S,4S)-l-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4- (methoxymethyl)pyrrolidin-2-yl]-lH-imidazol-5-yl}-l,ll- dihydroisochromeno[4',3':6,7]naphtho[l,2-d]imidazol-2-yl)-5-methylpyrrolidin-l-yl]-3-methyl- 1 -oxobutan-2-yl} carbamate A solution of tert-butyl (2S,4S)-2-[5-(2- {(2S,5S)-l -[N-(methoxycarbonyl)-L-valyl]-5- methylpyrrolidin-2-yl}-l,l l-dihydroisochromeno[4',3':6,7]naphtho[l,2-d]imidazol-9-yl)-lH- imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-l -carboxylate (150 mg, 0.19 mmol) in 1.25 N HCI in EtOH (3 mL) was stirred overnight then heated to 50 °C for 3h. The reaction was concentrated and the crude material dissolved in DMF (2 mL). To this solution was added a solution of (R)-2- (methoxycarbonylamino)-2-phenylacetic acid (52 mg, 0.25 mmol) and COMU (90 mg, 0.21 mmol). To the resulting solution was added diisopropylethylamine (0.099 mL, 0.57 mmol). After stirring for 2h at room temperature, the reaction was quenched with IN HCI (0.200 mL) and purified by HPLC. After lyophilization, the TFA salt was dissolved in EtOAc and washed with saturated NaHCOs. The organic phase was dried over Na2S04 and concentrated. The free base was then dissolved in MeCN/H20 and lyophilized to afford methyl {(2S)-l -[(2S,5S)-2-(9- {2-[(2S,4S)-l - {(2R)-2- [(methoxycarbonyl)amino]-2-phenylacetyl} -4-(methoxymethyl)pyrrolidin-2-yl]-lH-imidazol-5-yl} - l , l l -dihydroisochromeno[4',3':6,7]naphtho[l ,2-d]imidazol-2-yl)-5-methylpyrrolidin-l -yl]-3-methyl- l -oxobutan-2-yl} carbamate (65 mg, 39%). LCMS-ESI+: calculated for C49H54N808: 882.4; observed [M+l ]+: 884.1. Diagnostic peaks in NMR 'H NMR (CD3OD): 8.28 (s, 1H), 8.21 (s, 1H), 8.04 (s, 1H), 7.91 -7.01 (m, 10H), 3.62 (s, 3H), 3.34 (s, 3H), 3.23 (s, 3H), 1.56 (d, 3H), 1.03 (d, 3H), 0.94 (d, 3H).

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2013/75029, 2013, A1 Location in patent: Page/Page column 207; 208

7
[ 487048-28-2 ]
[ 1377049-84-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 13 steps 1.1: hydrogenchloride / 1,4-dioxane / 16 h / 20 °C 1.2: 12 h / 20 °C 2.1: water; sodium hydroxide / tert-Amyl alcohol / 5.25 h / 0 °C / Cooling with ice 3.1: triethylamine / tetrahydrofuran / 0.75 h / 0 °C / Cooling with ice 4.1: water; sodium tetrahydroborate / tetrahydrofuran / 2 h / 0 °C / Cooling with ice 5.1: silver trifluoromethanesulfonate; 2,6-di-tert-butyl-pyridine / dichloromethane / 3 h / 0 - 20 °C / Cooling with ice 6.1: water; lithium hydroxide / tetrahydrofuran; methanol / 2 h / 20 °C 7.1: caesium carbonate / 4 h / 20 °C 8.1: pyridinium hydrobromide perbromide / dichloromethane; methanol / 1.75 h / 20 °C 9.1: caesium carbonate / 20 h / 50 °C 10.1: ammonium acetate / toluene; 2-methoxy-ethanol / 4.5 h / 110 °C 11.1: manganese(IV) oxide / dichloromethane / 13 h 12.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 1 h / 20 °C 13.1: N-ethyl-N,N-diisopropylamine; 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate / N,N-dimethyl-formamide / 2 h / 20 °C
	Multi-step reaction with 11 steps 1.1: hydrogenchloride / 1,4-dioxane; methanol / 16 h / 20 °C 1.3: 12 h / 20 °C 2.1: sodium hydroxide; water / tetrahydrofuran / 5 h / 0 °C 3.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 0.75 h / 0 °C 3.2: 2 h / 0 °C 4.1: 2,6-di-tert-butyl-pyridine; silver trifluoromethanesulfonate / 3 h / 0 - 20 °C 5.1: water; lithium hydroxide / methanol; tetrahydrofuran / 2 h / 20 °C 6.1: caesium carbonate / 2-methyltetrahydrofuran / 4 h / 20 °C 7.1: pyridinium hydrobromide perbromide / dichloromethane; methanol / 1.75 h / 20 °C 8.1: caesium carbonate / 2-methyltetrahydrofuran / 20 h / 50 °C 9.1: ammonium acetate / toluene; 2-methoxy-ethanol / 4.5 h / 110 °C 10.1: manganese(IV) oxide / dichloromethane / 13 h 11.1: hydrogenchloride / ethanol / 3 h / 50 °C 11.2: 2 h / 20 °C

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2013/75029, 2013, A1
[2]Current Patent Assignee: GILEAD SCIENCES INC - US2013/309196, 2013, A1

8
[ 1378388-30-7 ]
[ 1377049-84-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 12 steps 1: water; sodium hydroxide / tert-Amyl alcohol / 5.25 h / 0 °C / Cooling with ice 2: triethylamine / tetrahydrofuran / 0.75 h / 0 °C / Cooling with ice 3: water; sodium tetrahydroborate / tetrahydrofuran / 2 h / 0 °C / Cooling with ice 4: silver trifluoromethanesulfonate; 2,6-di-tert-butyl-pyridine / dichloromethane / 3 h / 0 - 20 °C / Cooling with ice 5: water; lithium hydroxide / tetrahydrofuran; methanol / 2 h / 20 °C 6: caesium carbonate / 4 h / 20 °C 7: pyridinium hydrobromide perbromide / dichloromethane; methanol / 1.75 h / 20 °C 8: caesium carbonate / 20 h / 50 °C 9: ammonium acetate / toluene; 2-methoxy-ethanol / 4.5 h / 110 °C 10: manganese(IV) oxide / dichloromethane / 13 h 11: hydrogenchloride / dichloromethane; 1,4-dioxane / 1 h / 20 °C 12: N-ethyl-N,N-diisopropylamine; 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate / N,N-dimethyl-formamide / 2 h / 20 °C
	Multi-step reaction with 10 steps 1.1: sodium hydroxide; water / tetrahydrofuran / 5 h / 0 °C 2.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 0.75 h / 0 °C 2.2: 2 h / 0 °C 3.1: 2,6-di-tert-butyl-pyridine; silver trifluoromethanesulfonate / 3 h / 0 - 20 °C 4.1: water; lithium hydroxide / methanol; tetrahydrofuran / 2 h / 20 °C 5.1: caesium carbonate / 2-methyltetrahydrofuran / 4 h / 20 °C 6.1: pyridinium hydrobromide perbromide / dichloromethane; methanol / 1.75 h / 20 °C 7.1: caesium carbonate / 2-methyltetrahydrofuran / 20 h / 50 °C 8.1: ammonium acetate / toluene; 2-methoxy-ethanol / 4.5 h / 110 °C 9.1: manganese(IV) oxide / dichloromethane / 13 h 10.1: hydrogenchloride / ethanol / 3 h / 50 °C 10.2: 2 h / 20 °C

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2013/75029, 2013, A1
[2]Current Patent Assignee: GILEAD SCIENCES INC - US2013/309196, 2013, A1

9
[ 1378388-35-2 ]
[ 1377049-84-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 11 steps 1: triethylamine / tetrahydrofuran / 0.75 h / 0 °C / Cooling with ice 2: water; sodium tetrahydroborate / tetrahydrofuran / 2 h / 0 °C / Cooling with ice 3: silver trifluoromethanesulfonate; 2,6-di-tert-butyl-pyridine / dichloromethane / 3 h / 0 - 20 °C / Cooling with ice 4: water; lithium hydroxide / tetrahydrofuran; methanol / 2 h / 20 °C 5: caesium carbonate / 4 h / 20 °C 6: pyridinium hydrobromide perbromide / dichloromethane; methanol / 1.75 h / 20 °C 7: caesium carbonate / 20 h / 50 °C 8: ammonium acetate / toluene; 2-methoxy-ethanol / 4.5 h / 110 °C 9: manganese(IV) oxide / dichloromethane / 13 h 10: hydrogenchloride / dichloromethane; 1,4-dioxane / 1 h / 20 °C 11: N-ethyl-N,N-diisopropylamine; 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate / N,N-dimethyl-formamide / 2 h / 20 °C
	Multi-step reaction with 9 steps 1.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 0.75 h / 0 °C 1.2: 2 h / 0 °C 2.1: 2,6-di-tert-butyl-pyridine; silver trifluoromethanesulfonate / 3 h / 0 - 20 °C 3.1: water; lithium hydroxide / methanol; tetrahydrofuran / 2 h / 20 °C 4.1: caesium carbonate / 2-methyltetrahydrofuran / 4 h / 20 °C 5.1: pyridinium hydrobromide perbromide / dichloromethane; methanol / 1.75 h / 20 °C 6.1: caesium carbonate / 2-methyltetrahydrofuran / 20 h / 50 °C 7.1: ammonium acetate / toluene; 2-methoxy-ethanol / 4.5 h / 110 °C 8.1: manganese(IV) oxide / dichloromethane / 13 h 9.1: hydrogenchloride / ethanol / 3 h / 50 °C 9.2: 2 h / 20 °C

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2013/75029, 2013, A1
[2]Current Patent Assignee: GILEAD SCIENCES INC - US2013/309196, 2013, A1

10
[ 1194059-42-1 ]
[ 1377049-84-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 1: silver trifluoromethanesulfonate; 2,6-di-tert-butyl-pyridine / dichloromethane / 3 h / 0 - 20 °C / Cooling with ice 2: water; lithium hydroxide / tetrahydrofuran; methanol / 2 h / 20 °C 3: caesium carbonate / 4 h / 20 °C 4: pyridinium hydrobromide perbromide / dichloromethane; methanol / 1.75 h / 20 °C 5: caesium carbonate / 20 h / 50 °C 6: ammonium acetate / toluene; 2-methoxy-ethanol / 4.5 h / 110 °C 7: manganese(IV) oxide / dichloromethane / 13 h 8: hydrogenchloride / dichloromethane; 1,4-dioxane / 1 h / 20 °C 9: N-ethyl-N,N-diisopropylamine; 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate / N,N-dimethyl-formamide / 2 h / 20 °C
	Multi-step reaction with 8 steps 1.1: 2,6-di-tert-butyl-pyridine; silver trifluoromethanesulfonate / 3 h / 0 - 20 °C 2.1: water; lithium hydroxide / methanol; tetrahydrofuran / 2 h / 20 °C 3.1: caesium carbonate / 2-methyltetrahydrofuran / 4 h / 20 °C 4.1: pyridinium hydrobromide perbromide / dichloromethane; methanol / 1.75 h / 20 °C 5.1: caesium carbonate / 2-methyltetrahydrofuran / 20 h / 50 °C 6.1: ammonium acetate / toluene; 2-methoxy-ethanol / 4.5 h / 110 °C 7.1: manganese(IV) oxide / dichloromethane / 13 h 8.1: hydrogenchloride / ethanol / 3 h / 50 °C 8.2: 2 h / 20 °C

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2013/75029, 2013, A1
[2]Current Patent Assignee: GILEAD SCIENCES INC - US2013/309196, 2013, A1

11
[ 1378393-23-7 ]
[ 1377049-84-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 10 steps 1: water; sodium tetrahydroborate / tetrahydrofuran / 2 h / 0 °C / Cooling with ice 2: silver trifluoromethanesulfonate; 2,6-di-tert-butyl-pyridine / dichloromethane / 3 h / 0 - 20 °C / Cooling with ice 3: water; lithium hydroxide / tetrahydrofuran; methanol / 2 h / 20 °C 4: caesium carbonate / 4 h / 20 °C 5: pyridinium hydrobromide perbromide / dichloromethane; methanol / 1.75 h / 20 °C 6: caesium carbonate / 20 h / 50 °C 7: ammonium acetate / toluene; 2-methoxy-ethanol / 4.5 h / 110 °C 8: manganese(IV) oxide / dichloromethane / 13 h 9: hydrogenchloride / dichloromethane; 1,4-dioxane / 1 h / 20 °C 10: N-ethyl-N,N-diisopropylamine; 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate / N,N-dimethyl-formamide / 2 h / 20 °C

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2013/75029, 2013, A1

12
[ 1378388-37-4 ]
[ 1377049-84-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1: water; lithium hydroxide / tetrahydrofuran; methanol / 2 h / 20 °C 2: caesium carbonate / 4 h / 20 °C 3: pyridinium hydrobromide perbromide / dichloromethane; methanol / 1.75 h / 20 °C 4: caesium carbonate / 20 h / 50 °C 5: ammonium acetate / toluene; 2-methoxy-ethanol / 4.5 h / 110 °C 6: manganese(IV) oxide / dichloromethane / 13 h 7: hydrogenchloride / dichloromethane; 1,4-dioxane / 1 h / 20 °C 8: N-ethyl-N,N-diisopropylamine; 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate / N,N-dimethyl-formamide / 2 h / 20 °C
	Multi-step reaction with 7 steps 1.1: water; lithium hydroxide / methanol; tetrahydrofuran / 2 h / 20 °C 2.1: caesium carbonate / 2-methyltetrahydrofuran / 4 h / 20 °C 3.1: pyridinium hydrobromide perbromide / dichloromethane; methanol / 1.75 h / 20 °C 4.1: caesium carbonate / 2-methyltetrahydrofuran / 20 h / 50 °C 5.1: ammonium acetate / toluene; 2-methoxy-ethanol / 4.5 h / 110 °C 6.1: manganese(IV) oxide / dichloromethane / 13 h 7.1: hydrogenchloride / ethanol / 3 h / 50 °C 7.2: 2 h / 20 °C

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2013/75029, 2013, A1
[2]Current Patent Assignee: GILEAD SCIENCES INC - US2013/309196, 2013, A1

13
[ 1378388-16-9 ]
[ 1377049-84-7 ]

Reference： [1]Patent: WO2013/75029,2013,A1
[2]Patent: US2013/309196,2013,A1
[3]Patent: CN106831737,2017,A
[4]Patent: CN106831737,2017,A
[5]Patent: CN107573355,2018,A

14
[ 1378391-45-7 ]
[ 50890-96-5 ]
[ 1377049-84-7 ]

Yield	Reaction Conditions	Operation in experiment
65 mg	Stage #1: tert-butyl (2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate With hydrogenchloride In ethanol at 50℃; for 3h; Stage #2: (2R)-2-[(methoxycarbonyl)amino]-2-phenylacetic acid With 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h;	CY A solution of tert-butyl (2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (150 mg, 0.19 mmol) in 1.25 N HCl in EtOH (3 mL) was stirred overnight then heated to 50° C. for 3 h. The reaction was concentrated and the crude material dissolved in DMF (2 mL). To this solution was added a solution of (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (52 mg, 0.25 mmol) and COMU (90 mg, 0.21 mmol). To the resulting solution was added diisopropylethylamine (0.099 mL, 0.57 mmol). After stirring for 2 h at room temperature, the reaction was quenched with 1N HCl (0.200 mL) and purified by HPLC. After lyophilization, the TFA salt was dissolved in EtOAc and washed with saturated NaHCO3. The organic phase was dried over Na2SO4 and concentrated. The free base was then dissolved in MeCN/H2O and lyophilized to afford methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (65 mg, 39%). LCMS-ESI+: calculated for C49H54N8O8: 882.4; observed [M+1]+: 884.1. Diagnostic peaks in NMR 1H NMR (CD3OD): 8.28 (s, 1H), 8.21 (s, 1H), 8.04 (s, 1H), 7.91-7.01 (m, 10H), 3.62 (s, 3H), 3.34 (s, 3H), 3.23 (s, 3H), 1.56 (d, 3H), 1.03 (d, 3H), 0.94 (d, 3H)

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - US2013/309196, 2013, A1 Location in patent: Paragraph 0491

15
[ 1377049-84-7 ]
methyl {(1R)-2-[(2S,4S)-2-(5-{2-[(2S,5S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5-methylpyrrolidin-2-yl]-11-oxo-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%	With pyridinium chlorochromate In dichloromethane at 20℃; for 120h;	GK To a solution of methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (0.19 g, 0.22 mmol) in CH2Cl2 (3 mL) was added pyridinium chlorochromate (0.48 g, 2.21 mmol). The resulting slurry was stirred at room temperature for 5 days. The reaction was diluted with MeOH and filtered. The filtrate was diluted with CH2Cl2 and washed with water and aqueous sodium bicarbonate (saturated). The aqueous layers were backextracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude oil was purified by reverse phase HPLC (Gemini, 10→55% MeCN/H2O (0.1% TFA)). The desired fractions were combined and concentrated under reduced pressure to remove volatile organics. The addition of aqueous sodium bicarbonate with stirring resulted in precipitation of a white solid. The precipitate was filtered through a membrane filter and washed with water. Drying under reduced pressure afforded methyl {(1R)-2-[(2S,4S)-2-(5-{2-[(2S,5S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5-methylpyrrolidin-2-yl]-11-oxo-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate (0.08 g, 39%). LCMS-ESI+: calc'd for C49H52N8O9: 896.39 (M+); Found: 897.72 (M+H+).

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - US2013/309196, 2013, A1 Location in patent: Paragraph 0673

16
C₃₄H₃₃NO₈ [ No CAS ]
[ 1377049-84-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: ammonium acetate / 2-methoxy-ethanol; toluene / 16 - 90 °C 2.1: pyridinium hydrobromide perbromide / dichloromethane; methanol / 3 h / 20 - 25 °C 3.1: potassium carbonate / tetrahydrofuran / 16 - 45 °C 4.1: ammonium acetate / 2-methoxy-ethanol; toluene / 90 - 95 °C 5.1: manganese(IV) oxide / dichloromethane / 16 h / 20 °C 5.2: 16 h / 20 °C 5.3: 4 h / 60 °C 6.1: ammonium hydroxide / dichloromethane; water / 0.17 h 7.1: 4-methyl-morpholine; 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride / dichloromethane / 16 h / 5 - 10 °C