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Chemical Structure| 1103738-19-7 Chemical Structure| 1103738-19-7

Structure of LX-4211 intermediate
CAS No.: 1103738-19-7

Chemical Structure| 1103738-19-7

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Product Details of [ 1103738-19-7 ]

CAS No. :1103738-19-7
Formula : C12H19NO6
M.W : 273.28
SMILES Code : O=C([C@H](O1)[C@@H](O)[C@@]2([H])[C@]1([H])OC(C)(C)O2)N3CCOCC3
MDL No. :MFCD25977365
InChI Key :ZHDDJWFZDNKWIC-REIXXSIJSA-N
Pubchem ID :25207258

Safety of [ 1103738-19-7 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302
Precautionary Statements:P280-P305+P351+P338

Application In Synthesis of [ 1103738-19-7 ]

* 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 [ 1103738-19-7 ]

[ 1103738-19-7 ] Synthesis Path-Downstream   1~3

  • 1
  • [ 110-91-8 ]
  • [ 1103738-17-5 ]
  • [ 1103738-19-7 ]
YieldReaction ConditionsOperation in experiment
64% With 4-methyl-morpholine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; In tetrahydrofuran; at 20℃; for 6.5h; To a solution of <strong>[1103738-17-5](3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid</strong> (5.0 g, 24.5 mmol) in THF (100 ML, 20×) was added TBTU (11.8 g, 1.5 equiv), N-methylmorpholine (NMM, 4.1 mL, 1.5 equiv) and the mixture was stirred at 20 C. for 30 min. Morpholine (3.2 mL, 1.5 equiv) was then added, and the reaction mixture was stirred at 20 C. for an additional 6h. The solid was filtered off by filtration and the cake was washed with THF (10 mL, 2× ×2). The organic solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (hexanes:EtOAc, from 1:4 to 4: 1) to afford 4.3 g of the desired morpholine amide (64%) as a white solid. 1H NMR (CDCl3), delta 6.02 (d, J=3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J=3.2 Hz, 1H), 4.58 (d, J=3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H).
64% To a solution of <strong>[1103738-17-5](3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid</strong> (5.0 g, 24.5 mmol) in THF (100 mL, 20×) was added TBTU (11.8 g, 1.5 equiv), N-methylmorpholine (NMM, 4.1 mL, 1.5 equiv) and the mixture was stirred at 20 C. for 30 min. Morpholine (3.2 mL, 1.5 equiv) was then added, and the reaction mixture was stirred at 20 C. for an additional 6 h. The solid was filtered off by filtration and the cake was washed with THF (10 mL, 2× ×2). The organic solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (hexanes:EtOAc, from 1:4 to 4:1) to afford 4.3 g of the desired morpholine amide (64%) as a white solid. 1H NMR (CDCl3), delta 6.02 (d, J=3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J=3.2 Hz, 1H), 4.58 (d, J=3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H)
64% 6. EXAMPLES Aspects of this invention can be understood from the following examples.6.1. Synthesis of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro [2.3-d][13]dioxol-5-yl)(morpholino)methanone To a 12L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler was charged L-(-)-xylose (504.40 g, 3.360 mol), acetone (5L, reagent grade) and anhydrous MgSO4 powder (811.23g, 6.740 mol / 2.0 equiv). The suspension was set stirring at ambient and then concentrated H2SO4 (50 mL, 0.938 mol / 0.28 equiv) was added. A slow mild exotherm was noticed (temperature rose to 24C over about 1 hr) and the reaction was allowed to stir at ambient overnight. After 16.25 hours, TLC suggested all L-xylose had been consumed, with the major product being the bis-acetonide along with some (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction mixture was filtered and the collected solids were washed twice with acetone (500 mL per wash). The stirring yellow filtrate was neutralized with concentrated NH4OH solution (39 mL) to pH = 8.7. After stirring for 10 min, the suspended solids were removed by filtration. The filtrate was concentrated to afford crude bis-acetonide intermediate as a yellow oil (725.23 g). The yellow oil was suspended in 2.5 L water stirring in a 5L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler. The pH was adjusted from 9 to 2 with 1N aq. HCl (142mL) and stirred at room temperature for 6 h until GC showed sufficient conversion of the bis-acetonide intermediate to (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction was neutralized by the addition of 50% w/w aq. K2HPO4 until pH=7. The solvent was then evaporated and ethyl acetate (1.25L) was added to give a white suspension which was filtered. The filtrate was concentrated in vacuo to afford an orange oil which was dissolved in 1 L methyl tert-butyl ether. This solution had KF 0.23 wt% water and was concentrated to afford (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol as an orange oil (551.23g, 86% yield, 96.7 area% pure by GC). 1H NMR (400 MHz, DMSO-d6)delta1.22 (s, 3 H) 1.37 (s, 3 H) 3.51 (dd, J=11.12, 5.81 Hz, 1 H) 3.61 (dd, J=11.12, 5.05 Hz, 1 H) 3.93 - 4.00 (m, 1 H) 3.96 (s, 1 H) 4.36 (d, J=3.79 Hz, 1 H) 4.86 (br. s., 2 H) 5.79 (d, J=3.54 Hz, 1 H). 13C NMR (101MHz, DMSO-d6) delta26.48, 27.02, 59.30, 73.88, 81.71, 85.48, 104.69, 110.73. To a solution of (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (25.0g, 131 mmol) in acetone (375 mL, 15X) and H2O (125 mL, 5X) was added NaHC03 (33.0g, 3.0 equiv), NaBr (2.8g, 20 mol%) and TEMPO (0.40g, 2 mol%) at 20C. The mixture was cooled to 0-5C and solid trichloroisocyanuric acid (TCCA, 30.5 g, 1.0 equiv) was then added in portions. The suspension was stirred at 20C for 24h. Methanol (20 mL) was added and the mixture was stirred at 20C for 1h. A white suspension was formed at this point. The mixture was filtered, washed with acetone (50 mL, 2X). The organic solvent was removed under vacuum and the aqueous layer was extracted with EtOAc (300 mL, 12X x3) and the combined organic layers were concentrated to afford an oily mixture with some solid residue. Acetone (125 mL, 5X) was added and the mixture was filtered. The acetone solution was then concentrated to afford the desired acid (<strong>[1103738-17-5](3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid</strong>) as a yellow solid (21.0g, 79%). 1H NMR (methanol-d4), delta 6.00 (d, J= 3.2 Hz, 1H), 4.72 d, J= 3.2 Hz, 1H), 4.53 (d, J= 3.2 Hz, 1H), 4.38 (d, J= 3.2 Hz, 1H), 1.44 (s, 3H), 1.32 (s, 3H). To a solution of <strong>[1103738-17-5](3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid</strong> (5.0g, 24.5 mmol) in THF (100 mL, 20X) was added TBTU (11.8g, 1.5 equiv), N-methylmorpholine (NMM, 4.1 mL, 1.5 equiv) and the mixture was stirred at 20C for 30 min. Morpholine (3.2 mL, 1.5 equiv) was then added, and the reaction mixture was stirred at 20C for an additional 6h. The solid was filtered off by filtration and the cake was washed with THF (10 mL, 2X x2). The organic solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (hexanes:EtOAc, from 1:4 to 4:1) to afford 4.3 g of the desired morpholine amide (64%) as a white solid. 1H NMR (CDCl3), 8 6.02 (d, J= 3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J= 3.2 Hz, 1H), 4.58 (d, J= 3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H).
64% To a solution of Morpholine (3.2 mL, 1.5 equiv) was then added, and the reaction mixture was stirred at 20C for an additional 6h. The solid was filtered off by filtration and the cake was washed with THF (10 mL, 2X x2). The organic solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (hexanes:EtOAc, from 1:4 to 4:1) to afford 4.3 g of the desired 24 morpholine amide (64%) as a white solid. 1H NMR (CDCl3), delta 6.02 (d, J = 3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J = 3.2 Hz, 1H), 4.58 (d, J = 3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H).
51.5% in room temperature,2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate (137 g, 426.7 mmol)With N-methylmorpholine (48 mL, 440 mmol)(3aS, 5R, 6S, 6aS) -6-hydroxy-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro [2,3-d] [1,3] dioxolane-5-carboxylic acid 1d (58.0 g, 284 mmol)In tetrahydrofuran (1000 mL)After stirring at room temperature for 30 minutes,Morpholine (38 mL, 436 mmol) was added,Stir for 8 hours.The solid was removed by filtration,Washed with tetrahydrofuran (200 mL x 3)The filtrate was collected and concentrated under reduced pressure. Purification by silica gel column chromatography [petroleum ether / ethyl acetate (v / v) = 2/1]The title compound 1e was obtained as a white solid (40.0 g, 51.5%).
48% With 4-methyl-morpholine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; In tetrahydrofuran; at 20℃; for 12h; To a suspension of 183 (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxole-5-carboxylic acid (9.0 g, 44.2 mmol) and 185 HBTU (25.1 g, 66.3 mmol, N,N,N?,N?-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate) in 13 tetrahydrofuran was added 186 4-methylmorpholine (7.3 mL, 66.3 mmol) at room temperature. After 1 hour, to the mixture was added 187 morpholine (5.8 mL, 66.3 mmol) at room temperature. After 12 hours, the resulting mixture was filtered and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated in vacuo and the crude material was purified by silica gel column chromatography to obtain the 188 title compound (5.8 g, 48%) as a yellow solid. 1H NMR (400 MHz, CD3OD) delta 6.01 (d, J=3.6 Hz, 1H), 5.10 (s, 1H), 4.59 (d, J=2.4 Hz, 1H), 4.57 (d, J=3.6 Hz, 1H), 4.47 (d, J=2.4 Hz, 1H), 3.85-3.62 (m, 6H), 3.53-3.49 (m, 2H), 1.49 (s, 3H), 1.33 (s, 3H). [M+H]+ 274.

  • 2
  • [ 109-02-4 ]
  • [ 1103738-17-5 ]
  • [ 1103738-19-7 ]
YieldReaction ConditionsOperation in experiment
82.6% With O?(1H?benzotriazol?1?yl)?N,N,N?,N??tetramethyluronium tetrafluoroborate; In tetrahydrofuran; at 20 - 30℃; The above obtained acid A (99.9 g, 0.49 mol) was added to a 3 L three-necked flask.Add 1 L of tetrahydrofuran, stir to dissolve,Add TBTU (235.76g, 0.74mol) in turnAnd N-methylmorpholine (NMM, 82 mL, 0.74 mol).The resulting reaction mixture was stirred at room temperature overnight. Filter the reaction solution,The filter cake was washed with 200 mL x 2 tetrahydrofuran.The filtrate was concentrated to dryness under reduced pressure at 35 to 45 C.400 mL of hexane was added to the obtained slurry.Heat to 60 ~ 70 C for 1 hour, and cool to room temperature for 2 hours.Then cool down to 0 ~ 10 C for 2 hours.Filtered white solid111.02 g, yield 82.6%.
48% With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; at 20℃; for 12h; To a solution of (3aS, 5R, 6S, 6aS) -6-hydroxy-2,2-dimethyltetrahydrofuro [3,2- d][1,3] dioxole-5-carboxylic acid To a suspension of HBTU (25.1 g, 66.3 mmol, N, N, N', N'-tetramethyl-O- (1H- benzotriazol- 1-yl) uronium hexafluorophosphate) 4-Methylmorpholine (7.3 mL, 66.3 mmol) was added. 1 After the time, morpholine (5.8mL, 66.3 mmol) was added to the mixture at room temperature. 12 After this time, theresulting mixture was filtered and the filter cake was washed with tetrahydrofuran. Thefiltrate was concentrated in vacuo and the crude material was purified by silica gelcolumn chromatography to give the title compound (5.8 g, 48%) as a yellow solid.
  • 3
  • [ 915095-89-5 ]
  • [ 1103738-19-7 ]
  • (4-chloro-3-(4-(3(S)-tetrahydrofuranyloxy)benzyl)phenyl)((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuran[2,3-d][1,3]dioxolan-5-yl)methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
88.4% Add Compound C-2 (10 g, 27.2 mmol) to a 250 mL three-necked flaskAnd 70mL of tetrahydrofuran, stir and dissolve.The resulting solution is cooled to -70 to -80 C,Slowly add n-butyllithium solution (2.5M THF solution) to the cooled solution.12.5 mL, 1.15 eq), and stirred at -70 to -80 C for 1 hour.Further, a solution of the compound B in tetrahydrofuran (8.5 g of B in 30 mL of tetrahydrofuran, 31.3 mmol, 1.15 eq) was added dropwise to the reaction mixture.The mixture was stirred at -70 to -80 C for 2 hours. The reaction solution is heated to -10 to 0 C.The reaction solution was diluted with a saturated aqueous solution of NH 4Cl (20 mL).Add ethyl acetate(100 mL × 2) The reaction quenching solution was extracted twice, and the ethyl acetate layer was combined.The organic layer was washed with saturated brine (100 mL).The organic layer was concentrated to dryness under reduced pressure at 40 to 50 C.The resulting solid was recrystallized from ethyl acetate and n-hexane.Having 11.4g of compoundD-2, yield 88.4%.
 

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