[ CAS No. 1611493-60-7 ] {[proInfo.proName]}

Name: 1611493-60-7|(2R,5S,13aR)-8-Hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide|98%
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Quality Control of [ 1611493-60-7 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1611493-60-7 ]

SDS Specification

Alternatived Products of [ 1611493-60-7 ]

Product Details of [ 1611493-60-7 ]

CAS No. :	1611493-60-7	MDL No. :	MFCD31536971
Formula :	C₂₁H₁₈F₃N₃O₅	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SOLUWJRYJLAZCX-LYOVBCGYSA-N
M.W :	449.38	Pubchem ID :	90311989
Synonyms :		Chemical Name :	(2R,5S,13aR)-8-Hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Calculated chemistry of [ 1611493-60-7 ]

Physicochemical Properties

Num. heavy atoms :	32
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.38
Num. rotatable bonds :	4
Num. H-bond acceptors :	8.0
Num. H-bond donors :	2.0
Molar Refractivity :	107.13
TPSA :	100.87 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.1 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.43
Log Po/w (XLOGP3) :	2.73
Log Po/w (WLOGP) :	2.36
Log Po/w (MLOGP) :	1.65
Log Po/w (SILICOS-IT) :	2.23
Consensus Log Po/w :	2.28

Druglikeness

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

Water Solubility

Log S (ESOL) :	-4.36
Solubility :	0.0196 mg/ml ; 0.0000437 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.5
Solubility :	0.0141 mg/ml ; 0.0000314 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-4.65
Solubility :	0.00999 mg/ml ; 0.0000222 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	4.87

Safety of [ 1611493-60-7 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P301+P312-P302+P352-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1611493-60-7 ]

* 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 [ 1611493-60-7 ]

[ 1611493-60-7 ] Synthesis Path-Downstream 1~19

1
[ 1616342-45-0 ]
[ 1611493-60-7 ]

Reference： [1]Patent: WO2018/229798,2018,A1
[2]Patent: WO2019/159199,2019,A1
[3]Patent: WO2020/3151,2020,A1

2
[ 1616340-94-3 ]
[ 1611493-60-7 ]

Yield	Reaction Conditions	Operation in experiment
85%	With lithium bromide; In tetrahydrofuran; at 60℃;Flow reactor;	A solution of (2R,5 S, l3aR )-8-methoxy -7 ,9-dioxo-N -(2,4,6-trifluorobenzyl)- 2, 3, 4, 5, 7,9, 13, l3a-octahydro-2,5-methanopyrido[r,2':4,5]pyrazino[2, l- b][l,3]oxazepine-l0-carboxamide (lie) (75g,0.237moles) in THF was then introduced in a Tube Flow Reactor and demethylated with Lithium bromide (30.98g, 0.356 moles) in THF at temperature of 60C. After a residence time of 15 mins, the reaction mass was cooled to RT, treated with 10% Aq. HC1 solution and extracted in dichloromethane. The organic layer was concentrated & solid was isolated in isopropyl alcohol to yield Compound (III). (0330) HPLC purity > 98.0% (0331) Yield > 85%w/w
	With magnesium bromide; In acetonitrile; at 50℃; for 0.166667h;	Step 4 To the crude reaction mixture of the previous step was added MgBr2 (0.258 g, 1.40 mmol). The reaction mixture was stirred at 50 C for 10 minutes, acidified with 10% aqueous HC1, and extract twice with dichloromethane. The combined organic phases were dried over MgS04, filtered, concentrated, and purified by silica gel chromatography (EtOH/dichlormethane) followed by HPLC (ACN H2O with 0.1 % TFA modifier) to afford compound 42: 1H~ M (400 MHz, DMSO-</6) delta 12.43 (s, 1H), 10.34 (t, J = 5.7 Hz, IH), 8.42 (s, 1H), 7.19 (t, J = 8.7 Hz, 2H), 5.43 (dd, ./' 9.5, 4.1 Hz, I H), 5.08 (s, i l l ). 4.66 (dd, ./ 12.9, 4.0 Hz, IH), 4.59 (s, 1 1 1 ). 4.56 4.45 (m, 2H), 4.01 (dd, J = 12.7, 9.7 Hz, IH), 1.93 (s, 4H), 1.83 (d, J ------ 12.0 Hz, I H), 1.56 (dt, J = 12.0, 3.4 Hz, I H). LCMS-ESI+ (m/z): [M+H]+ calculated for { · FontWeight="Bold" FontSize="10" ] NuGamma :Chi. : 450.13; found: 450.2.
	With lithium chloride; In 1-methyl-pyrrolidin-2-one; dichloromethane; at 75℃; for 2.5h;	Formula I Form III from Compound G-1aA solution of about 10% (w/w) Compound G-1a (2.5 g Compound 1001) in methylene chloride was concentrated to a residue under vacuum. LiCl (2.6 g, 7 equiv) followed by N-methyl-2-pyrrolidone (12.5 mL) was added to the resulting residue. The method of preparing compound G1-a can be determined by one skilled on the art, for example, as described in co-pending PCT Serial No. US2013/076367, filed Dec. 19, 2013 entitled, ?POLYCYCLIC-CARBAMOYLPYRIDONE COMPOUNDS AND THEIR PHARMACEUTICAL USE.? The mixture was heated to an internal temperature of approximately 75 C. After 2.5 hours, the reaction was cooled to approximately 20 C. Dichloromethane (12.5 mL) and 0.5M hydrochloric acid (12.5 mL) was added, and the resulting mixture stirred for 5 minutes. The phases were separated, and the organic layer was washed with 10% aqueous sodium chloride solution (twice) followed by water. This solution was concentrated while gradually adding 3 volumes of isopropyl alcohol portionwise (40 C. bath temperature, 200-230 torr vacuum). The resulting slurry was slowly cooled to 2-4 C. The product was filtered and deliquored and dried. Formula I Form III was isolated and characterized as discussed below.

Reference： [1]Patent: WO2019/159199,2019,A1 .Location in patent: Page/Page column 43; 44
[2]Patent: WO2014/100323,2014,A1 .Location in patent: Page/Page column 100-101
[3]Patent: US2015/366872,2015,A1 .Location in patent: Paragraph 0379; 0380

3
[ 1616340-75-0 ]
[ 1611493-60-7 ]

Reference： [1]Patent: WO2014/100323,2014,A1

4
[ 1335210-23-5 ]
[ 1611493-60-7 ]

Reference： [1]Patent: WO2014/100323,2014,A1
[2]Patent: WO2018/229798,2018,A1
[3]Patent: WO2019/159199,2019,A1

5
[ 1611493-60-7 ]
potassium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepin-8-olate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium acetate; In methanol; at 20℃;	Formula III Form I 406 mg of (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1?,2?:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide (25.2 mg) was combined with 200 mg potassium acetate and 5 mL of methanol at room temperature, resulting in a suspension. A sample of the suspension was filtered the next day for testing. After several days, solids suitable for single crystal X-ray crystallography were found in the filtrate and analyzed.

Reference： [1]Patent: US2015/366872,2015,A1 .Location in patent: Paragraph 0402; 0403

6
[ 1611493-60-7 ]
sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1‘,2’:4,5]pyrazino[2,1-b][1,3]oxazepin-8-olate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In ethanol; water; at 20 - 75℃; for 1.5h;	Formula II Form I (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1?,2?:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide (20 g) and ethanol (80 mL) were added to a reaction vessel and warmed to about 75 C. Aqueous sodium hydroxide (22 mL 2 M solution) was added over approximately 30 minutes, after which the slurry was cooled to approximately 20 C. over approximately one hour. Sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1?,2?:4,5]pyrazino[2,1-b][1,3]oxazepin-8-olate Form I was collected by filtration, washed with EtOH (50 mL) and dried under vacuum. 1H NMR (400 MHz, DMSO-d6) delta 10.63 (t, J=5.8 Hz, 1H), 7.88 (s, 1H), 7.29-7.07 (m, 2H), 5.20 (dd, J=8.6, 3.6 Hz, 1H), 5.09 (t, J=4.1 Hz, 1H), 4.52 (m, 3H), 4.35 (dd, J=12.8, 3.6 Hz, 1H), 3.87 (dd, J=12.7, 8.7 Hz, 1H), 2.03-1.80 (m, 3H), 1.76-1.64 (m, 2H), 1.50-1.40 (m, 1H).
	With sodium hydroxide; In ethanol; water; at 20 - 75℃; for 1.5h;	Synthesis sodium <strong>[1611493-60-7](2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin-8-olate</strong> (Formula II) <strong>[1611493-60-7](2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide</strong> (20 g) and ethanol (80 mL) were added to a reaction vessel and warned to about 75 C. Aqueous sodium hydroxide (22 mL 2 M solution) was added over approximately 30 minutes, after which the slurry was cooled to approximately 20 VC over approximately one hour. Sodium (2R,5SJ aR)-7,9-dioxo-I 0-((2,4,6- trifinorobenzyl)earhamoyI)-2.3 ,4, 5 ,7, , 13 , 13 a-octahydro-2, 5- metianopyrido[r,2,:4,5]pyfazino[2, l-b][l,33oxii7j pii-8-o[ate Form was collected by filtration, washed with EtO.H (50 mL) and dried under vacuum.5H NMR (400 MHz, DMSOd6) delta 10.63 (t, J = 5.8 Hz, 1H), 7.88 (s, 1H), 7.29 (0272) - 7.07 (m, 2H), 5.20 (dd, J~ 8.6, 3.6 Hz, 1H), 5.09 (t, J::: 4.1 Hz, I H), 4.52 (m, 311), 4.35 (dd, J- 12.8, 3.6 Hz, 1H)9 3.87 (dd, J= 12.7, .7 Hz, 1H), 2.03 - I.JO (m, 311), 1.76-1.64 (m, 2H), 1.50 - 1.40 (m, 1 H),
65 g	With sodium hydroxide; In methanol; water; at 25 - 30℃;	The recrystallized Bictegravir was dissolved in 500 ml methanol at 60-65C in a separate reaction flask. In another reaction flask 4.5 g sodium hydroxide was dissolved in 500 ml water at room temperature. Hot methanol solution was added into aq. sodium hydroxide solution slowly within 2-3 hours at room temperature and the crystallized solid suspension was stirred for 1 hour. The product was filtered, washed with 250 ml of water and then dried at 50-55C under reduced pressure for 15-20 hours to obtain Bictegravir Sodium.Yield: 65g

	With methanol; sodium hydroxide; In dichloromethane; at 25℃;Flow reactor;	A solution of Compound (III) (lOg, 0.022 moles) in MDC was mixed with a solution of sodium hydroxide (7. l2g,0. l78 moles) in methanol in Tube Flow Reactor at 25C with residence time of 10 mins to give Sodium salt of Compound (III). Particle size : d90 NMT 15 pm.
	With sodium hydroxide; In 2,2,2-trifluoroethanol; water; at 0℃; for 4h;	Bictegravir (1.50 g, e.g. prepared according to Example 42 of WO 2014/100323 Al) was dissolved in trifluoroethanol (30 mL) upon heating to 65 C. To the solution aqueous NaOH (1M, 3.6 mL) was dropwise added. Thereafter, the solution was cooled to 0 C in 4 hours, whereupon crystallization was observed at a temperature of approximately 40 C. The obtained suspension was further stirred at 0 C for 3 hours, before the crystals were collected by filtration and dried under vacuum (30 mbar) at 50 C for 15 hours to obtain crystalline Form II of bictegravir sodium (1.30 g).

Reference： [1]Patent: US2015/366872,2015,A1 .Location in patent: Paragraph 0393; 0394; 0395
[2]Patent: WO2015/196116,2015,A1 .Location in patent: Paragraph 0120; 0121
[3]Patent: WO2018/229798,2018,A1 .Location in patent: Page/Page column 18; 19
[4]Patent: WO2019/159199,2019,A1 .Location in patent: Page/Page column 44
[5]Patent: WO2019/154634,2019,A1 .Location in patent: Page/Page column 20

7
[ 1611493-60-7 ]
[ 77-92-9 ]
C₂₁H₁₈F₃N₃O₅*2C₆H₈O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; at 21℃; for 48h;	Formula I Citric Acid Co-Crystal Form I (2R,5 S,13 aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1?,2?:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide (131 mg) and citric acid (148 mg) were added to a glass vial. Tetrahydrofuran (1 mL) was added, the vial was capped, and the mixture was stirred at about 21 C. for two days. The vial was vented and the solvent was allowed to evaporate at about 21 C. unassisted. After eight weeks at room temperature, crystals were found in the vessel and were identified as a 1:2 Formula I citric acid co-crystal.

Reference： [1]Patent: US2015/366872,2015,A1 .Location in patent: Paragraph 0396; 0397

8
[ 1611493-60-7 ]
[ 110-17-8 ]
C₂₁H₁₈F₃N₃O₅*C₄H₄O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; at 21 - 45℃; for 60h;	Formula I Fumaric Acid Co-crystal Form I (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1?,2?:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide (131 mg) and fumaric acid (103 mg) were added to a glass vial. Tetrahydrofuran (1 mL) was added, the vial capped, and the suspension stirred at about 21 C. for two days. An additional 1 mL of tetrahydrofuran was added, and the mixture was heated to 45 C. After about 12 hours at 45 C. the mixture was found to be fully dissolved and was removed from the heat bath. The vial was vented, and the solvent left to evaporate at room temperature. After one day solids were observed in the vial and it was re-capped. After eight weeks large crystals were found in the capped vial and identified as a 1:1 Formula I fumaric acid co-crystal.

Reference： [1]Patent: US2015/366872,2015,A1 .Location in patent: Paragraph 0398; 0399

9
[ 1611493-60-7 ]
[ 144-62-7 ]
C₂₁H₁₈F₃N₃O₅*C₂H₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; at 21℃; for 48h;	Formula I Oxalic Acid Co-crystal Form I (2R,5 S,13 aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1?,2?:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide (147 mg) and oxalic acid (134 mg) were added to a glass vial. Tetrahydrofuran (1 mL) was added, the vial capped, and the resulting solution was stirred at about 21 C. for about two days. The vessel was vented, and the solvent was allowed to evaporate at room temperature unassisted. After one day solids were observed in the vial and it was re-capped. Two days later large crystals were found in the vial and were identified as a 1:1 Formula I oxalic acid co-crystal.

Reference： [1]Patent: US2015/366872,2015,A1 .Location in patent: Paragraph 0400; 0401

10
[ 214759-21-4 ]
C₁₄H₁₄N₂O₆ [ No CAS ]
[ 1611493-60-7 ]

Yield	Reaction Conditions	Operation in experiment
65 g		50 g of compound (1) was charged along with 500 ml of dimethyl carbonate followed by 52 g of N, N?-Carbonyl Diimidazole. The reaction mass was heated at 40-50C and maintained for 5 hours and then cooled to room temperature. 39.4 g of compound (6) was added to the reaction mass and stirred for 1 hour. 500 ml of water added to the reaction mass and extracted with 500 ml ethyl acetate. Then back extracted with ethyl acetate 500 ml one more time and washed combined organic layer with 50 ml iN HC1. The organic layer was washed with saturated sodium bicarbonate solution 250 ml followed by water 500 ml. The layer was partially concentrated, filtered and then the filtrate was distilled out completely. 150 ml of methanol was added to the residue and heated to 45-50C and maintained for 1 hour. Then cooled to 0-10C, filtered and washed with chilled methanol 50 ml and finally recrystallized from methanol to obtain Bictegravir.Yield-65 gHPLC Purity: > 99.5 %

Reference： [1]Patent: WO2018/229798,2018,A1 .Location in patent: Page/Page column 17; 19

11
[ 1110772-05-8 ]
[ 1611493-60-7 ]

Reference： [1]Patent: WO2018/229798,2018,A1

12
[ 1611493-60-7 ]
[ 21085-72-3 ]
C₃₄H₃₄F₃N₃O₁₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With silver carbonate; In acetonitrile; at 60℃;	Anomeric bromination of 1 with 33% HBr in acetic acid gave bromide 2 in 70% crystallized yield. Treatment of phenol 3 with bromide 2 in the presence of Ag2CO3in acetonitrile at 60 C. produced compound 4 in 75% yield after reverse phase chromatography. Deprotection of 4 with triethylamine in methanol/water gave clean conversion to glucuronic acid 5 (M15). The reaction was stopped at 90% conversion since the amount of 3 present in the reaction started to increase. The mixture was purified by reverse phase chromatography with 0.1% TFA in the chromatography solvent. The free acid was isolated after lyophilization, however it contained a significant amount of 3. It was discovered that the free acid 5 was unstable in either neutral oracidic conditions. The triethylamine salt of M15 (5) appeared to be stable. Another batch was purified using the same method as before but the TFA was neutralized with triethylamine before lyophilization. The compound was stable to the conditions but contained a large amount of triethylammonium trifluoroacetate. Not all salt was removed. The material was purified by reverse phase chromatography but without TFA in the solvent. After lyophilization the triethylamine salt of M15 (5) was isolated in high purity and 24% overall yield.

Reference： [1]Patent: US2019/224206,2019,A1 .Location in patent: Paragraph 0096; 0097

13
5-methoxy-6-(methoxycarbonyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-3-carboxylic acid [ No CAS ]
[ 1611493-60-7 ]

Reference： [1]Patent: WO2019/159199,2019,A1

14
methyl (Z)-2-((dimethylamino)methylene)-4-methoxy-3-oxobutanoate [ No CAS ]
[ 1611493-60-7 ]

Reference： [1]Patent: WO2019/159199,2019,A1

15
methyl (Z)-2-(((2,2-dimethoxyethyl)amino)methylene)-4-methoxy-3-oxobutanoate [ No CAS ]
[ 1611493-60-7 ]

Reference： [1]Patent: WO2019/159199,2019,A1

16
1-(2,2-dimethoxy-ethyl)-3-methoxy-4-oxo-1,4-dihydro-pyridine-2,5-dicarboxylic acid dimethyl ester [ No CAS ]
[ 1611493-60-7 ]

Reference： [1]Patent: WO2019/159199,2019,A1

17
[ 75-89-8 ]
[ 1611493-60-7 ]
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2’:4,5]pyrazino[2,1-b][1,3]oxazepin-8-olate sodium 2,2,2-trifluoroethanol solvate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In water; at 65℃; for 2h;	(0212) Bictegravir (0.5 g, e.g. prepared according to Example 42 of WO 2014/100323 Al) was dissolved in trifluoroethanol (10 mL) upon heating to 70 C. To the solution aqueous NaOH (1M, 1.22 mL) was added and the solution was further stirred at 65 C for two hours. Thereafter, the solution was allowed to cool to room temperature, whereupon a suspension was obtained. The suspension was further stirred at room temperature for 5 hours before the crystals were collected by centrifugation in order to obtain bictegravir sodium trifluoroethanol solvate.

Reference： [1]Patent: WO2019/154634,2019,A1 .Location in patent: Page/Page column 23

18
[ 214759-21-4 ]
[ 1611493-60-7 ]

Reference： [1]Patent: WO2020/3151,2020,A1

19
lithium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin-8-olate [ No CAS ]
[ 1611493-60-7 ]

Yield	Reaction Conditions	Operation in experiment
78%	With hydrogenchloride; In methanol; water; at 20 - 30℃; for 1h;pH 2 - 3;	Charged Lithium (2R,5S,l3aR)-7,9-dioxo-l0-((2,4,6-trifluorobenzyl) carbamoyl)- 2,3,4,5,7,9,l3,l3a-octahydro-2,5-methanopyrido[l',2':4,5]pyrazino[2,l-b] [1,3] oxazepin-8- olate and Methanol(l60 ml). Reaction mass pH was adjusted to 2.0 to 3.0 with Cone HC1 at 20-30C, stirred for 1 hour and concentrated. Concentrated mass was diluted with methanol (160 ml) and heated to 60-65 C, stirred for 1 hour, cooled to 0-5 C and stirred for 4 hours to crystallize the product. The product was filtered, washed with chilled methanol and dried to yield the title compound.Yield- 78%; Purity by HPLC (by chromatography): 99.44%.

Reference： [1]Patent: WO2020/3151,2020,A1 .Location in patent: Page/Page column 21

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[ 1611493-60-7 ]

A1006402[ 1807988-02-8 ]

Bictegravir sodium

Reason: Free-salt

Ghs Precautionary Statements

Precautionary Statements-General
Code	Phrase
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Prevention
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P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

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Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
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

[ CAS No. 1611493-60-7 ] {[proInfo.proName]}

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[ 1611493-60-7 ] Synthesis Path-Downstream 1~19

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