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[ CAS No. 1051375-16-6 ] {[proInfo.proName]}

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Chemical Structure| 1051375-16-6
Chemical Structure| 1051375-16-6
Structure of 1051375-16-6 * Storage: {[proInfo.prStorage]}
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Product Details of [ 1051375-16-6 ]

CAS No. :1051375-16-6 MDL No. :MFCD20488027
Formula : C20H19F2N3O5 Boiling Point : -
Linear Structure Formula :- InChI Key :RHWKPHLQXYSBKR-BMIGLBTASA-N
M.W : 419.38 Pubchem ID :54726191
Synonyms :
S/GSK1349572;GSK1349572

Calculated chemistry of [ 1051375-16-6 ]

Physicochemical Properties

Num. heavy atoms : 30
Num. arom. heavy atoms : 12
Fraction Csp3 : 0.35
Num. rotatable bonds : 4
Num. H-bond acceptors : 7.0
Num. H-bond donors : 2.0
Molar Refractivity : 104.48
TPSA : 100.87 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.13 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.12
Log Po/w (XLOGP3) : 2.44
Log Po/w (WLOGP) : 1.66
Log Po/w (MLOGP) : 1.05
Log Po/w (SILICOS-IT) : 1.85
Consensus Log Po/w : 1.82

Druglikeness

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

Water Solubility

Log S (ESOL) : -4.01
Solubility : 0.041 mg/ml ; 0.0000979 mol/l
Class : Moderately soluble
Log S (Ali) : -4.2
Solubility : 0.0264 mg/ml ; 0.0000629 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -4.47
Solubility : 0.0142 mg/ml ; 0.0000339 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 4.16

Safety of [ 1051375-16-6 ]

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 [ 1051375-16-6 ]

* 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 [ 1051375-16-6 ]

[ 1051375-16-6 ] Synthesis Path-Downstream   1~3

  • 1
  • [ 1335210-35-9 ]
  • dolutegravir [ No CAS ]
YieldReaction ConditionsOperation in experiment
92% With lithium bromide; In tetrahydrofuran; methanol; isopropyl alcohol; at 60℃; for 6h;Large scale; (4S,l2aR)-N-(2,4-Difluorobenzyl)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8, l2,l2a- hexahydro-2H-pyrido[r,2':4,5]pyrazino[2, l-b][l,3]oxazine-9-carboxamide (3.9 Kg, 9.0 moles) was demethylated with Lithium bromide (1.56 kg, 18.0 moles) in Methanol / IP AJ THF at temperature of 60C. After 6 hrs, 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 (I). (0277) HPLC purity : 99.0% (0278) Yield : 92.0%. (0279) Chiral Purity: 99.0%
43% With magnesium bromide; In acetonitrile; at 50℃; for 30h; Compound 7 (480 mg, 1.11 mmol) was dissolved in 9.12 ml of acetonitrile and anhydrous MgBr2 (470 mg, 2.55 mmol) was added.The mixture was placed in a 50 C oil bath and stirred for 30 h, and the reaction mixture was a white suspension.The reaction was quenched by adding 11.4 ml of hydrochloric acid, and the reaction solution was clarified, and the reaction solution was diluted with CH 2 Cl 2 and the pH was adjusted to about 1,The organic phase was separated, and the aqueous layer was extracted twice again with 11.4 ml of CH2Cl2.Add 3 ml AcOEt to dissolve, suction filtration, wash with a small amount of ethyl acetate.Drying to obtain 0.37 g of a colorless solid product of Compound I;The crude product was recrystallized from ethyl acetate and ethanol to give the dolutegravir I 0.18g(Rf = 0.46, TLC developer: CH2Cl2 / MeOH = 40/1 + 0.5% HOAc),As a white solid,The yield was 43%; the HPLC purity was 98.5%.
1.5 g With lithium bromide; In isopropyl alcohol; at 70 - 80℃; for 15h; (4R, 12aS)-N-(2,4-difluorobenzyl)-7-methoxy-4-methyl-6,8-dioxo-3 ,4,6,8, 12, 12a,-hexahydro-2H- pyrido[l ' ;2' :4,5]pyrazino[2, l -b][l ,3]oxazine-9-carboxamide (XVIII) (2 g, 0.0046 moles) was suspended in isopropyl alcohol (20 ml) and lithium bromide (0.8 g, 0.00924 moles) was added and stirred at 70-80C for 15 h to complete the reaction. After completion of reaction the reaction mass was acidified with 5N aqueous hydrochloric acid (5 ml) and concentrated. DM Water (20 ml) was added to the concentrated mass and stirred at 25-30C to crystallize the product. The product was filtered, washed with DM Water and dried to yield Dolutegravir (I) ( 1.5 g, HPLC purity: 97.93%).
67 g Anhydrous MgBr2 (202.1 g) was added to a solution of (4R,12aS)-N-(2,4-difluorobenzyl)-7- methyoxy-4-methyl-6, 8-dioxo-3, 4,6,8, 12, 12a-hexahydro-2H-pyrido[ 1 ' ,2' :4,5]pyrazino[2, 1- b][l,3]oxazine-9-carboximide (formula la, 120 g) in acetonitrile (480 mL). The reaction mixture was heated to 50-52 C for 8 hours. The reaction mixture was then cooled to 25-35 C and the acetonitrile layer was siphoned out. Methylene dichloride (1800 mL) and dilute HC1 solution (240 mL HC1 + 1056 mL water) was added to the residual mass, and the solution was stirred. The organic layer was separated off, washed with water, and the solvent was distilled off under reduced pressure. The residue was crystallized from methanol to obtain dolutegravir (67 g)-
With magnesium bromide hexahydrate; at 80℃; for 2h; To the reaction flask was charged acetonitrile (700g) andCompound C (90 g, 0.228 mol);Stirring heated to 50 ,Add acetic acid (13.7g, 1eq);Warmed to 60 ~ 65 ,R-3-Amino-1-butanol (22.3 g, 1.1 eq) was added dropwiseAcetonitrile (100 g);The reaction was stirred for 15 hours to liquid phase compound (D)After HPLC purity 98.0%, magnesium bromide hexahydrate (199.7 g, 3 eq)Heated to 80 , stirred for 2h;After the reaction is completed,Into 3% hydrochloric acid (830g) and methylene chloride (1200g);Layered, the water layer into dichloromethane (600g; layered, the combined organic layer was concentrated to dryness, into ethanol,Concentrate again to dryness to give duloxeuma (90.9% yield).

  • 2
  • [ 1802141-49-6 ]
  • [ 1051375-16-6 ]
YieldReaction ConditionsOperation in experiment
85.44% With lithium bromide In tetrahydrofuran at 60 - 65℃; for 24h; 27 Example 27: Preparation of compound (la) (n =2) Example 27: Preparation of compound (la) (n =2) To a solution of compound (Ila) (l lg, 0.025 moles) in THF (1 10 ml) was added anhydrous LiBr (32.0 g, 0.37 moles). The reaction mixture was heated to 60- 65°C for 24 hours. A solution of acetic acid (40 ml) in water (1 10 ml) was added and the reaction mixture was extracted in MDC (50 ml). The organic layer was washed with water and the solvent was distilled off under reduced pressure. The reaction mixture was stirred in methanol (75 ml) for 1 hour at room temperature. The solid was isolated by filtration, washed with methanol and dried to afford 8.8 g of titled compound Efficiency: 85.44 %
85% With lithium bromide In tetrahydrofuran for 8h; Reflux; Large scale; 12-14 Example 14: (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-hydroxy-4-methyl -6,8-Dioxo-2H-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxamide 3.35kg of compound (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-ethoxy-4- Methyl-6,8-dioxo-2H-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxamide (1.0eq ) and 3.25 kg of anhydrous lithium bromide (5.0 eq) were added to 40.00 L of tetrahydrofuran. The mixture was refluxed and reacted for 8 hours. After the reaction was completed, it was concentrated under reduced pressure, and 13.40 L of ethanol was added at 20 to 30° C. to stir and dissolve, 1.25 L of concentrated hydrochloric acid was added to acidify, and 77.00 L of purified water was added. After 130 minutes, filtered, purified and dried to obtain 2.67 kg of dolutegravir (yield: 85.0%).
66% Stage #1: C22H23F2N3O5 With sodium hydroxide In ethanol; lithium hydroxide monohydrate at 90 - 100℃; for 10h; Stage #2: With hydrogenchloride In lithium hydroxide monohydrate at 20 - 25℃; for 0.25h; 46 Example 46 Preparation of Dolutegravir Aqueous sodium hydroxide solution (3eq, 53 mg in 0.66 mL of water) was added to compound of Formula XIB (wherein R=ethyl) (200 mg, l eq) in ethanol (2 mL, 10V) at 20-25°C. The reaction mass was heated to 90-100°C and stirred for 10 hrs. After reaction completion, the reaction mass was filtered and water (10V) was added to the obtained solid. pH of the reaction mass was adjusted to ~4 by using dilute hydrochloric acid then stirred for 15 min at 20-25°C. The solid obtained was filtered and washed with water. Finally the compound was triturated with diisopropylether(l OV) to get the title compound (120 mg, 66%). Purity by HPLC: 88%, MS (ES): m/z 420 (M+H)+.
  • 3
  • [ 1051375-16-6 ]
  • [ 112-64-1 ]
  • [ 2248029-86-7 ]
YieldReaction ConditionsOperation in experiment
82.8% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0℃; for 24h; Inert atmosphere;
80% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; for 16h; Inert atmosphere; 1 Hydroxyl group deprotonation and coupling to fatty acid Dolutegravir (DTG) (2 g, 4.768 mmol, 1.0 equiv.) was dissolved in anhydrousdimethylformamide (20 mL) and cooled to 0°C under argon. N,N diisopropylethylamine(1.66 mL, 9.536 mmol, 2.0 equiv.) was then added dropwise to the precooled solution ofthe drug. Myristoyl chloride (1.30 mL, 9.536 mmol, 2.0 equiv.) was then added to thedeprotonated phenol solution. The mixture was gradually warmed to room temperatureunder stirring over 16 hours, concentrated, and purified by flash chromatography elutingwith 80 % EtOAc/Hex to give the prodrug in a chemical yield of 80%. The ‘H-NMRspectrum of modified DTG prodrug (MDTG) showed the presence of a broad peak at1.21-1.50 ppm and peaks corresponding to the aliphatic protons on the fatty acid moiety.
Stage #1: (4R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1’,2’:4,5]pyrazino[2,1-b] [1,3]oxazine-9-carboxamide With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: tetradecanoyl chloride In N,N-dimethyl-formamide at 0 - 25℃; for 16h;
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0℃; for 18h; Inert atmosphere;

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