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Chemical Structure| 1051375-19-9
Chemical Structure| 1051375-19-9
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Product Details of [ 1051375-19-9 ]

CAS No. :1051375-19-9 MDL No. :MFCD28405599
Formula : C20H18F2N3NaO5 Boiling Point : -
Linear Structure Formula :- InChI Key :UGWJRRXTMKRYNK-VSLILLSYSA-M
M.W : 441.36 Pubchem ID :46216142
Synonyms :
S/GSK1349572 sodium;GSK-1349572A
Chemical Name :Sodium (4R,12aS)-9-((2,4-difluorobenzyl)carbamoyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazin-7-olate

Safety of [ 1051375-19-9 ]

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 [ 1051375-19-9 ]

* 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 [ 1051375-19-9 ]

[ 1051375-19-9 ] Synthesis Path-Downstream   1~61

  • 1
  • dolutegravir [ No CAS ]
  • [ 1051375-19-9 ]
YieldReaction ConditionsOperation in experiment
99% With sodium hydroxide; In ethanol; water; at 20 - 80℃;Product distribution / selectivity; After dissolution of 18.0 g of compound 12 (1.0 eq.) in 54 mL of EtOH by heating, followed by filtration, 21.5 mL of 2N NaOHaq.(1.0 eq.) was added to the solution at 80 0C. The solution was gradually cooled to room temperature. Filtration, washing with 80 mL of EtOH and drying provided 18.8 g of compound 13 (99% yield) as a crystal. 1H NMR(300 MHz, DMSO-d6) delta 10.70 (t, J = 6.0 Hz, 1H), 7.89 (s, 1 H), 7.40-7.30 (m, 1 H), 7.25-7.16 (m, 1H), 7.06-6.98 (m, 1H), 5.22-5.12 (m, 1H), 4.87-4.74 (m, 1H), 4.51 (d, J = 5.4 Hz, 2H), 4.35-4.25 (m, 1 H), 4.16 (dd, J = 1.8, 14.1 Hz, 1 H), 4.05-3.90 (m, 1H), 3.86- 3.74 (m, 1 H), 2.00-1.72 (m, 1 H), 1.44-1.32 (m, 1 H), 1.24 (d, J = 6.9 Hz, 3H).
99% With sodium hydroxide; In ethanol; at 80℃; After dissolution of 18.0 g of compound 12 (1.0 eq.) in 54 mL of EtOH by heating, followed by filtration, 21.5 mL of 2N NaOHaq. (1.0 eq.) was added to the solution at 80 C. The solution was gradually cooled to room temperature. Filtration, washing with 80 mL of EtOH and drying provided. 18.8 g of compound 13 (99% yield) as a crystal.
99% With propylene glycol; sodium t-butanolate; In toluene; at 70℃; Example 1 (co-solvent: toluene) 500 mg (1 .2 mmol) DTG free acid was suspended at RT in a mixture of racemic 1 ,2-PG (6.3 mL) and toluene (2.5 ml). The suspension was heated to 70 C. A solution of 1 17 mg (1 .4 mmol, 1 .0 eq.) sodium tert-butylate in 1 .2 mL 1 ,2-PG was added dropwise to the suspension. After completion of the addition, a clear yellow solution was obtained. The heating of the oil bath was turned off and the solution was allowed to cool down to room temperature (RT). A solid started to precipitate within 5-10 min. The mixture was stirred O/N and the solid was isolated by filtration, washed with acetone and dried at 50 C / 10 mbar for 24 hours. DTG- Na 1 ,2-PG solvate was obtained in 99% yield (607 mg).
96% With sodium ethanolate; In ethanol; at 24 - 26℃; for 2h; Example 6: Preparation of dolutegravir sodium form SEtoH/H2o A suspension of dolutegravir (2.004 g, 4.8 mmol, for example prepared in accordance with the procedures disclosed in examples 1 a to 1 k of WO 2010/068253 A1 ) in 80 ml. ethanol was adjusted to a temperature of 25 ± 1 C. Solid sodium ethoxide (assay: 95%, 0.516 g, 7.2 mmol) was added and the obtained suspension was further stirred at 25 ± 1 C for 2 h. Finally, the crystals were collected by filtration and dried at RT under vacuum (20-30 mbar) for 42 h to obtain 2.105 g of dolutegravir sodium form SEtoH/H2o- Yield: 96% of theory; Karl-Fischer titration: 0.9%; TGA: -3.4% (25-120 C, 10 C/min)
90.27% With sodium hydroxide; In tetrahydrofuran; methanol; at 60 - 65℃; for 1h; Example 28: Preparation of sodium salt of compound (la) (n =2) The compound (la) (8.8 g, 0.021 moles) was dissolved in methanol (10 vol) at 60- 65C. To the reaction mixture was added 2N aqueous NaOH solution (8.68 ml) and stirred further for 1 hour. The reaction mixture was cooled to room temperature and stirred for 1 hour. The solid was isolated by filtration, washed with methanol and dried to offered 8.4 g of titled compound Efficiency: 90.27 %
90% With methanol; sodium hydroxide; In dichloromethane; at 25℃;Flow reactor; Large scale; A solution of Compound (I) ( 3.0 kg, 7.16 moles)in MDC was mixed with a solution of sodium hydroxide (0.48 kg, 12.17 moles )in methanol in Tube Flow Reactor at 25C with residence time of 10 mins to give Sodium salt of Compound (I). (0266) HPLC purity : 99.0% (0267) Yield : 90.0%. (0268) Particle size :d90 NMT lOpm.
88% With sodium hydroxide; In ethanol; water; at 80℃; Reference examples The starting material can be prepared by any known method for the preparation of Dolutegravir and Dolutegravir sodium. Dolutegravir (also referred to as Dolutegravir free acid) can for example be prepared by processes disclosed in US8217034 and Dolutegravir sodium Form I can for example be prepared by processes disclosed in WO 2010/068253. For example, a slurry mixture of Dolutegravir (0.9 g, 1 eq), EtOH (16 mL) and water (1 mL) was heated to 80 C and stirred for 30 min. NaOH 2N (1.22 mL, 1.05 eq) was added dropwise and the mixture became completely clear then precipitation was obtained. The solution was cooled to room temperature and stirred for 2 hours. The product was collected by vacuum filtration, washed with EtOH (5 mL) and dried to obtain 0.83 g of slightly yellow solid (88% yield).
71% With sodium hydroxide; In ethanol; water; at 80 - 85℃; for 0.333333h; Sodium hydroxide powder (8.94 g, l Oeq) was added to the compound of Formula XIB (wherein R=ethyl) (10 g, leq) in ethanol (50 mL, 5V) and DMSO (25 ml, 2.5 V) at 20-25C and stirred for 5-6 hrs. After reaction completion, the reaction mass was filtered and washed with ethanol (2V). The obtained solid was suck dried and acidified with aqueous hydrochloric acid at 0-5C. The solid formed was filtered off, washed with water (5V) and suck dried under vacuum for 10 min. The resulting solid was dried under vacuum at 50-55c for 1 h (7.5 g). Ethanol (10V) was added to the obtained solid and heated to 80-85C. 2N sodium hydroxide solution (1 eq, 714 mg dissolved in 8.9 mL water) was added to the reaction mass at 80-85C and stirred for 10-20 min. The reaction mass was cooled to 20-25C. The solid obtained was filtered off, washed with ethanol then dried under vacuum to get the title compound (7 g, 71% Yield). Purity by HPLC: 99.83%
With sodium hydroxide; In methanol; butan-1-ol; at 25 - 40℃;Large scale; Example 12: Preparation of crystalline dolutegravir sodium Form-M4. (0071) Dolutegravir (2.0 kg) was dissolved in a mixture of 1-butanol (1000 L) and methanol (30 L) at 70-80 C to produce a clear solution. The clear solution was cooled to 50-55 C, filtered through a Hyflo bed at 50-55 C, and washed with 1-butanol (2 L). The clear solution was reheated to 50- 55 C and cooled to 37-40 C. To this, 0.25 N methanolic sodium hydroxide solution (2 L) was added at 37-40 C. The reaction mass was cooled to 25-30 C and stirred at 25-30 C for 15-18 hours to precipitate the product. The obtained solid was filtered, washed with 1-butanol (4 L), and dried under vacuum at 100 C for 16 hours. The sample was then milled and dried at 130 C under vacuum for 18-24 hours. The resulting solid was identified as crystalline dolutegravir sodium Form- M4.
52 g With sodium hydroxide; In methanol; butan-1-ol; for 16h; Dolutegravir (50 g) was dissolved in n-butanol (2500 mL) and methanol (750 mL). The reaction mass was filtered through filter paper and a methanolic sodium hydroxide solution (5.25 g NaOH in 500 mL methanol) was added to the filtrate. The suspension was stirred for 16 hours and filtered. The solid was then dried at 100 C, milled and further dried at 130 C to obtain dolutegravir sodium (52 g).
90 g With sodium hydroxide; In pentan-1-ol; at 22 - 28℃; for 40h; Dolutegravir (100 g) was added to 1-pentanol (1500 ml) at 25-35C. To this mixture, 6.6N sodium hydroxide solution (39.73 ml) was slowly added at 22-28C, then the reaction mass was stirred for about 40 hrs at 22-28C. The solid obtained was filtered, washed with 1-pentanol and suck dried. The suck dried material was initially dried at 25-35C for 2 hrs under vacuum, further at 50-55C for 10 hrs under vacuum and finally dried at 100-110C for 16 hrs under vacuum. The dried compound was kept in a air tray drier at 25-35C for about 6 hrs yielded dolutegravir sodium Form-L9. Yield: 90 grams
10 g With sodium hydroxide; In methanol; water; at 0 - 30℃; for 1.5h; Dolutegravir base 10 g was charged with 100 ml methanol to the reactor at 25-30C andcooled to 0-5C. Aqueous sodium hydroxide (NaOH) (2 g in 11 ml water) was added toreaction mass within 30 minutes at 0-5C and maintained for 1 hour at 0-5C. The reactionmass was filtered and washed with 2 volumes of methanol. The mass obtained was then dried under vacuum at 55C.Dryweight- lOg

  • 3
  • [ 1335210-26-8 ]
  • [ 1051375-19-9 ]
  • 4
  • C13H16ClNO7 [ No CAS ]
  • [ 1051375-19-9 ]
  • 5
  • C10H16ClNO5 [ No CAS ]
  • [ 1051375-19-9 ]
  • 6
  • C8H12ClNO3 [ No CAS ]
  • [ 1051375-19-9 ]
  • 7
  • 1-(2,2-dimethoxy-ethyl)-3-methoxy-4-oxo-1,4-dihydro-pyridine-2,5-dicarboxylic acid dimethyl ester [ No CAS ]
  • [ 1051375-19-9 ]
  • 8
  • 1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydro-pyridine-2,5-dicarboxylic acid dimethyl ester boron complex [ No CAS ]
  • [ 1051375-19-9 ]
  • 10
  • C16H18BNO11 [ No CAS ]
  • [ 1051375-19-9 ]
  • 11
  • C18H21BN2O10 [ No CAS ]
  • [ 1051375-19-9 ]
  • 12
  • [ 1335210-35-9 ]
  • [ 1051375-19-9 ]
YieldReaction ConditionsOperation in experiment
90% With methanol; sodium hydroxide; In butan-1-ol; at 100℃;Flow reactor; Large scale; A solution of (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 (Ila) (3.9 Kg, 9.0 moles) in n-butanol was mixed with a solution of sodium hydroxide (3.6 kg, 90.0 moles) in methanol in Tube Flow Reactor at l00C with residence time of 20 mins to yield Sodium salt of Compound (I). (0260) HPLC purity : 99.0% (0261) Yield : 90.0%. (0262) Particle size :d90 NMT 15 pm.
90 g (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-3-methyl-6-(methyloxy)-5,7-dioxo- 2,3,5, 7, 11,11 a-hexahydro[ 1 ,3 ]oxazolo[3 ,2-a]pyrido[ 1 ,2-d]pyrazine-8- carboxamide (100 gm) was dissolved in acetonitrile (1000 mL) and magnesium bromide hexahydrate (161 gm) was added. The mixture was heated to 80C for 2 hours, quenched with HC1 and then extracted with methylene dichloride. Methanol (1452 mL) and n-butanol (4840 mL) was added at a temperature of 27C and then the temperature of the reaction mass was raised to 77C. Stirred the reaction mass for 1 hour at the same temperature to get a clear solution. The reaction mass was cooled to a temperature of 37C and then methanolic sodium hydroxide was slowly added. Cooled the reaction mass to 25C and stirred for 20 hours. The product was filtered, washed with n-butanol and dried under vacuum (90 gm).
  • 14
  • C16H21F2NO4 [ No CAS ]
  • [ 1051375-19-9 ]
  • 15
  • C14H17F2NO4 [ No CAS ]
  • [ 1051375-19-9 ]
  • 16
  • C15H19F2NO4 [ No CAS ]
  • [ 1051375-19-9 ]
  • 17
  • C18H25F2NO4 [ No CAS ]
  • [ 1051375-19-9 ]
  • 19
  • C12H13F2NO3 [ No CAS ]
  • [ 1051375-19-9 ]
  • 20
  • C16H21F2NO3 [ No CAS ]
  • [ 1051375-19-9 ]
  • 22
  • C17H22F2N2O5 [ No CAS ]
  • [ 1051375-19-9 ]
  • 23
  • C21H30F2N2O5 [ No CAS ]
  • [ 1051375-19-9 ]
  • 25
  • C20H20F2N2O6 [ No CAS ]
  • [ 1051375-19-9 ]
  • 26
  • C22H23F2N3O5 [ No CAS ]
  • [ 1051375-19-9 ]
  • 27
  • C16H20F2N2O3 [ No CAS ]
  • [ 1051375-19-9 ]
  • 36
  • [ 1206102-11-5 ]
  • [ 1051375-19-9 ]
YieldReaction ConditionsOperation in experiment
98.9% General procedure: Example 4 (General Procedure) Examples 4a, 4b, 4d and 4e: 1 .00 g (1 .96 mmol) DTG-OBn was suspended in 10 mL racemic 1 ,2-PG and 5 mL of a co-solvent. The flask was flushed with argon and then charged with 42 mg of 10% palladium on activated charcoal (50% wet, 0.20 mmol, 0.01 eq.). The resulting mixture was heated to 50 C and stirred under hydrogen atmosphere until completion. The flask was flushed with argon and the warm mixture was filtered over glass fiber filter. The filtrate was charged into a clean flask and heated to the desired temperature (see Table below). A solution of 192 mg (1 .96 mmol, 1 .0 eq.) sodium tert-butylate in 2 ml. racemic 1 ,2-PG was added to the mixture, under vigorous stirring. After completion of the addition, a clear yellow solution was obtained. A solid started to precipitate within 5 min. After stirring for 5-15 min, the heating of the oil bath was turned off and after 90 min (T (oil bath) = approx. 30C), the oil bath was removed, the mixture was stirred for another 30 min at RT and then filtered. The isolated solid was washed with acetone and dried at 50C under vacuum (10 mbar) for different times (see table) yielding Dolutegravir sodium salt (1 :1 ) 1 ,2-propylene glycol solvate as off-white solid.
  • 45
  • dimethyl-1-allyl-3-methoxy-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate [ No CAS ]
  • [ 1051375-19-9 ]
  • 46
  • C16H18BNO10 [ No CAS ]
  • [ 1051375-19-9 ]
  • 47
  • 1-allyl-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid [ No CAS ]
  • [ 1051375-19-9 ]
  • 48
  • methyl 1-allyl-5-(2,4-difluorobenzylcarbamoyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate [ No CAS ]
  • [ 1051375-19-9 ]
  • 49
  • methyl 5-(2,4-difluorobenzylcarbamoyl)-3-methoxy-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2-carboxylate [ No CAS ]
  • [ 1051375-19-9 ]
  • 50
  • methyl (E)-2-(((2,2-dimethoxyethyl)amino)methylene)-4-methoxy-3-oxobutanoate [ No CAS ]
  • [ 1051375-19-9 ]
  • 51
  • 1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate boron [ No CAS ]
  • [ 1051375-19-9 ]
  • 53
  • methyl-5-carbamoyl-1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate [ No CAS ]
  • [ 1051375-19-9 ]
  • 54
  • (4R,12aS)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazine-9-carboxamide [ No CAS ]
  • [ 1051375-19-9 ]
  • 55
  • C10H15NO4 [ No CAS ]
  • [ 1051375-19-9 ]
  • 56
  • [ 1246616-65-8 ]
  • [ 1051375-19-9 ]
  • 57
  • C21H20O6S [ No CAS ]
  • [ 1051375-19-9 ]
  • 58
  • [ 1206102-05-7 ]
  • [ 1051375-19-9 ]
  • 59
  • 5-methoxy-6-(methoxycarbonyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-3-carboxylic acid [ No CAS ]
  • [ 1051375-19-9 ]
  • 60
  • methyl (Z)-2-((dimethylamino)methylene)-4-methoxy-3-oxobutanoate [ No CAS ]
  • [ 1051375-19-9 ]
  • 61
  • methyl (Z)-2-(((2,2-dimethoxyethyl)amino)methylene)-4-methoxy-3-oxobutanoate [ No CAS ]
  • [ 1051375-19-9 ]
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