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[ CAS No. 125995-13-3 ] {[proInfo.proName]}

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Chemical Structure| 125995-13-3
Chemical Structure| 125995-13-3
Structure of 125995-13-3 * Storage: {[proInfo.prStorage]}
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Quality Control of [ 125995-13-3 ]

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Product Details of [ 125995-13-3 ]

CAS No. :125995-13-3 MDL No. :MFCD07369252
Formula : C14H27NO4 Boiling Point : -
Linear Structure Formula :- InChI Key :HWSHVKNLMBMKSR-GHMZBOCLSA-N
M.W : 273.37 Pubchem ID :2734288
Synonyms :

Calculated chemistry of [ 125995-13-3 ]

Physicochemical Properties

Num. heavy atoms : 19
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.93
Num. rotatable bonds : 6
Num. H-bond acceptors : 5.0
Num. H-bond donors : 1.0
Molar Refractivity : 73.54
TPSA : 70.78 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.17 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.17
Log Po/w (XLOGP3) : 1.13
Log Po/w (WLOGP) : 1.98
Log Po/w (MLOGP) : 1.14
Log Po/w (SILICOS-IT) : 1.95
Consensus Log Po/w : 1.87

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.85
Solubility : 3.85 mg/ml ; 0.0141 mol/l
Class : Very soluble
Log S (Ali) : -2.21
Solubility : 1.68 mg/ml ; 0.00616 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.53
Solubility : 0.812 mg/ml ; 0.00297 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 4.09

Safety of [ 125995-13-3 ]

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 [ 125995-13-3 ]

* 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 [ 125995-13-3 ]

[ 125995-13-3 ] Synthesis Path-Downstream   1~35

  • 1
  • [ 125971-86-0 ]
  • [ 125971-96-2 ]
  • [ 125971-95-1 ]
YieldReaction ConditionsOperation in experiment
96.5% With Trimethylacetic acid; In toluene; at 105 - 110℃; for 1h;Industrial scale; 1 kg (4R-cis) 6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester, 6 L of toluene, 0.41 kg was placed in a 10 L dry clean reaction kettle. Pivalic acid,Stir at room temperature for 1 hour; add 1.1 kg to the reactor2-[2-(4-Fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide, refluxed at elevated temperature (105 ° C-110 °C) to the end of the reaction(TLC detection and tracking, the developing solvent was ethyl acetate: petroleum ether = 1:2).Stop heating, cool down to 25 ° C - 30 ° C, and add 5 L of saturated sodium bicarbonate solution to wash once.The organic phase was washed twice with 2*5 L of purified water, then the organic phase was transferred to a rotary evaporator and concentrated to dryness under reduced pressure at 60 ° C.4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-isopropyl)-3-phenyl-4-[(aniline)hydroxyl]-1H-Pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxolan-4-acetic acid tert-butyl ester.The crude product was mixed with 4 L of isopropanol and heated to reflux. After the solution was dissolved, it was naturally cooled to room temperature, kept for half an hour, then cooled to 0 ° C to 5 ° C, stirred for 1 hour with heat, filtered with suction, and rinsed with 1 L of petroleum ether. Filter cake, dry, get4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-isopropyl)-3-phenyl-4-[(aniline)hydroxyl]-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxolan-4-acetic acid tert-butyl ester boutique 1.54kg, yield 96.5percent, purity 99.3percent .
75.1 - 79% With Trimethylacetic acid; In tetrahydrofuran; for 40 - 72h;Heating / reflux; To a 100 ML 3 necked round bottom flask equipped with thermometer, condenser and magnetic stirrer, was added compound 16 (6.12 g, 22.4 mmol), pivalic acid (1.15 g, 11.25 mmol), 1,4-diketone 9 (6.99 g, 16.7 mmol) and THF (37 ml). The mixture was refluxed for 40 h. After cooling, the reaction mixture was concentrated on a rotary evaporator. The brown oily residue was dissolved in ethanol (45 ML) with heating. Then, water (18. 5 ML) was added dropwise. The mixture was cooled slowly to room temperature and then stirred for another 3 h. The solid was filtered off and washed with a 5: 2 mixture of ethanol and water, then dried at 55°C overnight to give the title compound as an off-white solid (8.66 g, 79.0percent).
72.3% With Trimethylacetic acid; In tetrahydrofuran; n-heptane; toluene; for 48h;Heating / reflux; To a 1L reactor equipped with thermometer, condenser and mechanic stirrer, was added compound 16 (30. 0 g, 0.109 mole), pivalic acid (5.17 g, 0.05 mole), 1,4 diketone 9 (35.2 g, 0.085 mole) and a 2: 2: 3 mixture of heptane: toluene: THF (180 ml). The mixture was refluxed for 48 hr and then cooled to 25°C. The solvents were evaporated. The brown oil residue was dissolved in ethanol (240 ML) by heating to 63 °C. Then, water (96 ml) was added dropwise over 120 min. When the solution became turbid, it was cooled slowly to room temperature and stirred over night. The precipitated solid was filtered, washed with 5: 2 ethanol: water (180 ML) and dried at 60°C for 22 HR, to give the title compound as on off-white solid (40.24 g, 72.3percent).
triethylamine; Trimethylacetic acid; In tetrahydrofuran; hexane; at 50℃;Heating / reflux;Product distribution / selectivity; Example 1 : Triethylammonium pivalate as catalyst; hexane: THF as solvent; Schematic:Diketone of atorvastatin (1.09 eq, 84.4g) is added to a solution of l,l-dimethyl-(4R- cw)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxane-4-acetate [TBIN] (50.69g, 185.4 mmol) in THF (112.6 g) and hexane (42.7 g) and the mixture warmed to 5O0C under an N2 atmosphere. At 50°C pivalic acid (0.7 eq, 13.3g) is added, followed by triethylamine (0.7 eq., 13.2 g) and the resulting suspension heated at reflux under a nitrogen atmosphere until reaction completion, with concomitant removal of water.On completion the reaction mixture is cooled to 25°C before addition of MTBE (157 g). The solution is washed with a 5.5 percent (w/w) solution of KOH, then a 3.5 percent (w/w) of HCl, separated and then the organic layer is vacuum distilled with stirring to a thick oil. At the distillation end-point acetone (100 ml) and IPA (100ml) were added and the mixture was heated to 5O0C until a solution is achieved. Water (50ml) was added to the solution and the mixture was allowed to cool to room temperature over two hours, then cooled to 0°C and stirred for 1 hr. The crystals were isolated by filtration and washed with IPA (50ml at 00C). The product was dried in a vacuum oven maintaining the temperature at <40°C.
hydrogenchloride; triethylamine; In tetrahydrofuran; tert-butyl methyl ether; at 50℃;Heating / reflux;Product distribution / selectivity; Example 9: Triethylammonium hydrochloride as catalyst; MTBE :THF as solvent; Diketone of atorvastatin (1.09 eq, 8.32 g) is added to a solution of l,l-dimethyl-(4R- cfs)-6-(2-ammoethyl)-2,2-dimethyl-l,3-dioxane-4-acetate (5 g, 18.3 mmol) in MTBE (6.7g) and THF (5.4 g) and the mixture warmed to 500C under an N2 atmosphere. At 500C triethylamine (0.7 eq, 1.29g) is added, followed by 36percent hydrogen chloride (0.7 eq, 1.30 g) and the resulting suspension heated at reflux under a nitrogen atmosphere until reaction completion, with concomitant removal of water.
triethylamine; Trimethylacetic acid; In tetrahydrofuran; tert-butyl methyl ether; at 50℃;Heating / reflux;Product distribution / selectivity; Example 2: Triethylammonium pivalate as catalyst; MTBE: THF as solvent; Diketone of atorvastatin (1.09 eq, 84.4g) is added to a solution of l,l-dimethyl-(4R- m)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxane-4-acetate (50.69g, 185.4 mmol) inTHF (57.7 g) and MTBE (99.4 g) and the mixture warmed to 500C under an N2 atmosphere. At 50°C pivalic acid (0.7 eq, 13.3g) is added, followed by triethylamine (0.7 eq., 13.2 g) and the resulting suspension heated at reflux under a nitrogen atmosphere until reaction completion, with concomitant removal of water.On completion the reaction mixture is cooled to 25°C before addition of MTBE (157 g). The solution is washed with a 5.5 percent (w/w) solution of KOH (230 ml), then a 3.5 percent (w/w) of HCl (250 ml), separated and then the organic layer is vacuum distilled with stirring to a thick oil. At the distillation end-point acetone (100 ml) and IPA (100ml) were added and the mixture was heated to 50°C until a solution is achieved. Water(50ml) was added to the solution and the mixture was allowed to cool to room temperature over two hours, then cooled to 0°C and stirred for 1 hr. The crystals were isolated by filtration and washed with IPA (50ml at 0°C). The product was dried in a vacuum oven maintaining the temperature at <40°C.
N-ethyl-N,N-diisopropylamine; Trimethylacetic acid; In toluene; at 50℃;Heating / reflux;Product distribution / selectivity; Example 4: Diisopropylethylammonium pivalate as catalyst; toluene as solvent; Diketone of atorvastatin (1.09 eq, 8.32 g) is added to a solution of l,l-dimethyl-(4R- cw)-6-(2-aminoethyl)-2,2-dirnethyl-l,3-dioxane-4-acetate (5.Og, 18.3 mmol) in Toluene (13 g) and the mixture warmed to 5O0C under an N2 atmosphere. At 50°C pivalic acid (0.7 eq, 1.15 g) is added, followed by diisopropylethylamine (0.7 eq., 1.65 g) and the resulting suspension heated at reflux under a nitrogen atmosphere until reaction completion, with concomitant removal of water
sodium hydroxide; Trimethylacetic acid; In toluene; at 50℃;Heating / reflux;Product distribution / selectivity; Example 8: Sodium pivalate as catalyst; Toluene as solvent; Diketone of atorvastatin (1.09 eq, 5.03 g) is added to a solution of l,l-dimethyl-(4R- c/s)-6-(2-aminoethyl)-2,2 -dimethyl- l,3-dioxane-4-acetate (3 g, 10.9 mmol) in toluene (8.65g) and the mixture warmed to 50°C under an N2 atmosphere. At 500C pivalic acid (0.7 eq, 0.69g) is added, followed by 50percent sodium hydroxide (0.61 g, 7.6 mmol) and the resulting suspension heated at reflux under a nitrogen atmosphere until reaction completion, with concomitant removal of water.
sodium hydroxide; Trimethylacetic acid; In tetrahydrofuran; tert-butyl methyl ether; at 50℃;Heating / reflux;Product distribution / selectivity; Example 6: Sodium pivalate as catalyst; MTBE:THF as solvent; Diketone of atorvastatin (1.09 eq, 8.32 g) is added to a solution of l,l-dimethyl-(4R- m)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxane-4-acetate (5 g, 18.3 mmol) in THF (5.3 g) and MTBE (6.7g). and the mixture warmed to 50°C under an N2 atmosphere. At 50°C pivalic acid (0.7 eq, 0.34g) is added, followed by 50percent sodium hydroxide (1 g, 12.5 mmol) and the resulting suspension heated at reflux under a nitrogen atmosphere until reaction completion, with concomitant removal of water.
zinc diacetate; In tetrahydrofuran; tert-butyl methyl ether; at 50℃;Heating / reflux;Product distribution / selectivity; Example 5: Zinc acetate as catalyst; MTBE :THF as solvent; Diketone of atorvastatin (1.09 eq, 8.3g) is added to a solution of l,l-dimethyl-(4R- c/5')-6-(2-aminoethyl)-252-dimethyl-l,3-dioxane-4-acetate (5.0g, 18.5 mmol) in THF (5.7 g) and MTBE (6.7g). Zinc acetate (1.59g, 12.9 mmol) is added and the resulting suspension then heated at reflux under a nitrogen atmosphere until reaction completion, with concomitant removal of water.
N-ethylmorpholine;; Trimethylacetic acid; In toluene; at 50℃;Heating / reflux;Product distribution / selectivity; Example 3: N-ethylmorpholine pivalate as catalyst; Toluene as solvent; Diketone of atorvastatin (1.09 eq, 8.32 g) is added to a solution of l,l-dimethyl-(4R- cw)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxane-4-acetate (5.Og, 18.3 mmol) in Toluene (13 g) and the mixture warmed to 50°C under an N2 atmosphere. At 50°C pivalic acid (0.7 eq, 1.15 g) is added, followed by n-ethylmorpholine (0.7 eq., 1.47 g) and the resulting suspension heated at reflux under a nitrogen atmosphere until reaction completion, with concomitant removal of water.
calcium hydroxide; Trimethylacetic acid; In tetrahydrofuran; tert-butyl methyl ether; at 50℃;Heating / reflux;Product distribution / selectivity; Example 7: Calcium pivalate as catalyst; MTBE:THF as solvent; Diketone of atorvastatin (1.09 eq, 8.32 g) is added to a solution of l,l-dimethyl-(4R- c/5)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxane-4-acetate (5 g, 18.3 mmol) in THF(5.3 g) and MTBE (6.7g). and the mixture warmed to 500C under an N2 atmosphere. EPO <DP n="13"/>At 500C pivalic acid (0.7 eq, 1.15g) is added, followed by calcium hydroxide (0.47 g, 6.35mmol) and the resulting suspension heated at reflux under a nitrogen atmosphere until reaction completion, with concomitant removal of water.
80.0 grams of (4R-cis)-1 ,1-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-1 ,3- dioxane-4-acetate, 1200 ml of cyclohexane and 104 grams of (+/-)-4-fluoro-alpha-2- methyl-1-oxopropyl-gamma-oxo-N-beta-diphenyl benzene were stirred at 25-3O0C for 15-20 EPO <DP n="10"/>minutes. 16 grams of pivalic acid were added, and then the reaction mass was heated to reflux under azeotropic conditions until completion of the reaction. The solvent was evaporated below 7O0C under reduced pressure, lsopropyl alcohol (160 ml) was added and evaporated under reduced pressure. 400 ml of isopropyl alcohol was added to the residue below 500C, then the mixture was cooled to 25- 3O0C for about 6-8 hours. The mixture was further cooled to 0-10°C and stirred for 2-3 hours. The separated solid was filtered and washed with 160 ml of isopropyl alcohol. The obtained solid was dried at 60-70°C to yield 120 grams of the title compound
With Trimethylacetic acid; In tetrahydrofuran; hexane; at 75℃; for 96h;Product distribution / selectivity; Example 1: (Comparative)50 g tert-butyl isopropylidene (TBIN), prepared as described in Tetrahedron Letters, 1992, 2279, 13.25 g wet sponge nickel catalyst, 28percent ammonia solution (137.5 ml) and 375 ml isopropyl alcohol (IPA) are added to a pressure vessel. The mixture is reduced with 50 psi of hydrogen, then filtered and concentrated in vacuo. The resulting oil is dissolved in 250 ml warm toluene, water washed and again concentrated in vacuo to give an amino ester. The amino ester, 85 g 4-fluoro-alpha-(2- methyl-l-oxopropyl)-gamma-oxo-N,beta-diphenyl-benzenebutanamide (diketone of atorvastatin), 12.5 g pivalic acid, 137.5 ml tetrahydrofuran (THF) and 137.5 ml hexanes are charged to an argon inerted pressure vessel which is sealed and heated to 750C for 96 hours. After cooling the solution is diluted with 400 ml methyl tert- butyl ether (MTBE) and washed firstly with dilute aqueous sodium hydroxide followed by dilute aqueous hydrochloric acid. The mixture is then concentrated in vacuo to give an acetonide ester.The acetonide ester is dissolved in 275 ml warm methanol and aqueous hydrochloric acid (5 g of 37percent hydrochloric acid in 75 ml of water) is added. The mixture is stirred at 300C to produce a diol ester. 100 ml methyl tert-butyl ether and aqueous sodium hydroxide (150 ml of H2O and 25 g of 50percent aqueous sodium hydroxide) are then added and the mixture stirred at 3O0C to produce a sodium salt. 600 ml water is added and the mixture washed twice with 437.5 ml methyl tert-butyl ether. Residual methyl tert-butyl ether and some methanol is removed from the aqueous layer by atmospheric distillation to a temperature of 87-9O0C. The mixture is stirred at 75-850C for 18 hours, then cooled, acidified and extracted into 875 ml toluene. The mixture is heated at reflux for 4 hours and water is removed azeotropically. After cooling, the mixture is filtered and washed with toluene. The crude lactone is then recrystallised from toluene and lactone is isolated as an white solid.Yield: 36 g ; 59.8percent from tert-butyl isopropylidene. Impurity level: crude Methyl ester 1.3 percent. pure Methyl ester 0.6 percent.; Example 2 50 g tert-butyl isopropylidene (TBIN), prepared as described in Tetrahedron Letters,1992, 2279, 13.25 g wet sponge nickel catalyst, 28percent ammonia solution (137.5 ml) and 375 ml isopropyl alcohol (IPA) are added to a pressure vessel. The mixture is reduced with 50 psi of hydrogen, then filtered and concentrated in vacuo. The resulting oil is dissolved in 250 ml warm toluene, water washed and again concentrated in vacuo to give an amino ester. The amino ester, 85 g 4-fluoro-alpha-(2- methyl-l-oxopropyl)-gamma-oxo-N,beta-diphenyl-benzenebutanamide (diketone of atorvastatin prepared by a method disclosed in United States Patent Number 5,155,251 which is herein incorporated by reference and Bauman K.L, Butler D.E., Deering C.F., et al Tetrahedron Letters 1992;33:2283-2284), 12.5 g pivalic acid, 137.5 ml tetrahydrofuran (THF) and 137.5 ml hexanes are charged to an argon inerted pressure vessel which is sealed and heated to 750C for 96 hours. After cooling the solution is diluted with 400 ml methyl tert-butyl ether (MTBE) and washed firstly with dilute aqueous sodium hydroxide followed by dilute aqueous EPO <DP n="9"/>hydrochloric acid. The mixture is then concentrated in vacuo to give an acetonide ester.The acetonide ester is dissolved in 275 ml warm methanol and aqueous hydrochloric acid (5 g of 37percent hydrochloric acid in 75 ml of water) is added. The mixture is stirred at 3O0C to produce a diol ester. 100 ml methyl tert-butyl ether and aqueous sodium hydroxide (150 ml of H2O and 25 g of 50percent aqueous sodium hydroxide) are then added and the mixture stirred at 3O0C to produce a sodium salt. 600 ml water is added and the mixture washed twice with 437.5 ml methyl tert-butyl ether.In this case, the mixture is distilled under atmospheric pressure to a batch temperature of 70-750C. A vacuum of approximately -0.25 bar is then applied and distillation is continued until the methanol content of the mixture is reduced to less than 2.6percentw/v. The batch is stirred at 75-85°C for 18 hours, then cooled, acidified and extracted into 875 ml toluene. The mixture is heated at reflux for 4 hours and water removed azeotropically. After cooling the mixture is filtered, washed with toluene and dried directly. Lactone is isolated as awhite solid.Yield: 37.9 g ; 63percent from tert-butyl isopropylidene. Impurity level : Methyl ester 0.16percent.; Example 3 50 g tert-butyl isopropylidene (TBIN), prepared as described in Tetrahedron Letters, 1992, 2279, 13.25 g wet sponge nickel catalyst, 28percent ammonia solution (137.5 ml) and 375 ml isopropyl alcohol (IPA) are added to a pressure vessel. The mixture is reduced with 50 psi of hydrogen, then filtered and concentrated in vacuo. The resulting oil is dissolved in 250 ml warm toluene, water washed and again concentrated in vacuo to give an amino ester. ...
With Trimethylacetic acid; In cyclohexane; at 20℃;Heating / reflux; Diketo compound (V) (1.50 g) was taken in cyclohexane (10 ml) at room temperature. Amino ketal compound (FV) (1.00 g) in cyclohexane was added followed by the addition of pivalic acid (0.11 g). The reaction mixture was refluxed and after the completion of the reaction, reaction mixture was cooled and the precipitate filtered. Dried the material in vacuum oven at 50-550C for 2 hr (moisture content is approx. 0.5 percent) to get crude compound III, which was recrystallized in isopropyl alcohol to give pure compound III as a solid. Compound III (1.40 gm) was then taken into methanol (20 ml) and stirred followed by the addition of dilute hydrochloric acid. Reaction mixture was warmed and stirred. After the completion of the reaction, reaction mixture was cooled and water was added. The precipitated material was filtered and dried under vacuum at 50-550C for 12 hrs to afford the desired product II.
In a 2 L round bottom flask equipped with a mechanical stirrer and temperature monitoring facility, Stetter compound i.e. 4-(4-Fluorophenyl)-2-isobutryl-4-oxo-N- phenyl butryl amide (100 g, 0.24 mole) and Amino side chain i.e. [6-(2-aminoethyl)-2,2-dimethyl-[l,3]dioxan-4-yl]-acetic acid tert-butyl ester (261.9 g, 0.96 mole) was added at 25-35 0C. To this reaction vessel 2 L cyclohexane, 100 ml THF and Pivalic acid (11.0 g, 0.11 mole) were added under same temperature condition. The reaction mixture was heated up to reflux temperature 70-85 °C and the reflux was maintained for 18 hrs. After cooling the reaction mixture to room temperature (25-35 0C), 500 ml water was added and stirred for 20 min. To this reaction mixture Liq. Ammonia was added to adjust the pH between 8.5-9.5 and stirred for 30 min. at room temperature.Now for separating the layers, aq. layer is extracted with 2 x 500 ml MDC. From the combined MDC and cyclohexane layer, MDC and cyclohexane were distilled out. At <n="8"/>this stage weight of the residue was 389.0 g. Now 720 ml IPA was added in to reaction mixture and the temperature raised up to 50-60 0C within 1 hr. Stirred for 30 min. at 50-60 0C. Slowly 327 ml water was added at 50-60 0C within 1 hour and then cooled down to room temperature 25-35 0C. Further stirred for 5 hrs at the same temperature and then filtered and washed with 50 ml x 2 mixture of IPA and water (11:5). Finally dried for 12 hrs at 50-550C to obtain 117.3 g dry cake of (4R-cis)-6-[-2-[3-phenyl-4- (phenyl-carbamoyl)-2-(4-flourophenyl)-5-(l-methyl-ethyl)-pyrrol-l-yl]-ethyl]-2,2-di methyl-[l,3]dioxane-4-yl-acetic acid-tertriay butyl ester (Atorvastatin protected diol).
Trimethylacetic acid; In 2-methyl THF; for 30 - 35h;Heating / reflux; (4R-6R)-6-aminoethyl-2,2-dimethyl-l,3-dioxane-4-acetic acid tert-hvXyl ester (compound of formula IV) (50gms); 2-[2-(4-Fluoro-rhohenyl)-2-oxo-l-phenyl-ethyl]-4-methyl- 3-oxo-pentanoic acid phenylamide (compound of formula V) (68.9 gm); pivalic acid (11.96 gm) and 2-Methyl THF (750 ml) were stirred with reflux, water is removed through dean stark apparatus during the course of reaction. The mixture was refluxed for about 30-35 hours. After cooling, the reaction mixture was concentrated. Thus obtained oily residue is dissolved in 2-propanol (350 ml) with heating. The mixture cooled slowly to room temperature and stirred for 2 hours, further cooled to 15-200C and stirred for one hour. The solid precipitate out which is filtered, washed with IPA and dried at 600C overnight to give the title compound as off white solid (63 gm; Purity: >99 percent).(4R-6R)-6-aminoethyl-2,2-dimethyl-l,3-dioxane-4-acetic acid tert-butyl ester (compound of formula IV) (50 gms); 2-[2-(4-Fluoro-phenyl)-2-oxo-l-phenyl-ethyl]-4- methyl-3-oxo-pentanoic acid phenylamide (compound of formula V) (68.9 gm); pivalic acid (11.96 gm) and 2-Methyl THF (750 ml) were stirred with reflux, water is removed through dean stark apparatus during the course of reaction. Thus obtained oily residue is dissolved in 2-propanol (350 ml) with heating. Water (138 ml) was added drop wise. The reaction mixture was cooled slowly till reaches room temperature and stirred for 2 hours. The solid precipitate out which is filtered, washed with 2- propanol and dried overnight at 600C to give [R-(R*, EPO <DP n="13"/>R*)]-2-(4-fluorophenyl)-beta,delta-dioxane-5-(l-metlalphaylethyl)-3-phenyl-4-[(phenylaralphaino) carbonyl]-lH-pyrrole-l-heptanoic acid tert-butyl ester as off white solid, (63 gm; Purity:- >99 percent).(4R-6R)-6-amialphaoethyl-2,2-dimethyl-l,3-dioxane-4-acetic acid tert-butyl ester (compound of formula IV) (50 gms); 2-[2-(4-Fluoro-phenyl)-2-oxo-l-phenyl-ethyl]-4- methyl-3-oxo-pentanoic acid phenylamide (compound of formula V) (68.9 gm); pivalic acid (11.96 gm) and 2-Methyl THF (750 ml) were stirred and refulx. The water is removed during the course of reaction. After reaction completion, about (400 ml )of solvent was distilled out and then cooled to 25-300C, stirred for 2 hours further cooled to 10-150C, Stirred for 30 minutes and filtered, washed with 2- methyl THF (100 ml), and dried at 55-600C overnight to give the title compound as an off white solid. (60 gm; Purity: >99 percent).
With Trimethylacetic acid; In cyclohexane; at 20 - 78℃; EXAMPLE 5: 58g (4R-cis)- 1 , 1 -dimethylethyl-6-(2-aminomethyl)-2,2-dimethyl- 1 ,3 -dioxane-4-acetate is charged with 480 ml of cyclohexane at RT followed by the addition of 84 g of DKT III and 12 g of pivalic acid at RT. The reaction mass is heated to reach at 78°C and water is removed azeotropically. Reaction is maintained for 62 hrs and is monitored. After the completion, reaction mass is quenched with sodium bicarbonate solution. Organic layer separated is washed thoroughly till it is free from acidity. Cyclohexane from the organic layer is recovered under vacuum. Residue so obtained is dissolved in isopropanol and product is isolated by the addition of water at 30-35°C.Product is further purified from isopropanol.
(4R-cis)-1,1-dimethylethyl-6-{2-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrol-1 yl]ethyl}-2,2-dimethyl-1,3-dioxane-4-acetate (Compound H) A mixture of (4R-cis)-1,1-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-1, 3-dioxane]-4-acetate (9 Kg, 32.96 moles), (+-)- 4-fluoro-alpha-(2-methyl-1-oxopropyl)-y-oxo-N,beta-diphenylbenzenebutaneamide (13.33 Kg, 31.93 moles), n-heptane (90 L), tetrahydrofuran (22.5 L), toluene (22.5 L) and pivalic acid (2.18 Kg, 21.30 moles) was heated to reflux temperature for about 40 hrs. The reaction was monitored for completion by HPLC. The reaction mass was cooled and diluted with toluene. The reaction mixture was then washed initially with aqueous sodium hydroxide solution (0.5 N), then with aqueous hydrochloric acid solution (0.5 N) and followed by brine (10percent). The organic layer was treated with activated carbon, and filtered through a hyflo filter. The organic layer was concentrated to 10percent of the total volume under vacuum. Isopropyl alcohol (34 L) was then added, and the solvent recovered under vacuum, followed by repeated addition of isopropyl alcohol and solvent recovery under vacuum. The residue was dissolved in isopropyl alcohol and de-ionized water (45 L) was added till turbidity appeared. Further de-ionized water (60 L) was added gradually. The precipitated product was filtered, washed with a mixture of isopropyl alcohol and de-ionized water (2:1) and dried to get the title compound (16.2 Kg, 24.77 moles, 94percent by HPLC). The crude product was purified by dissolving in isopropyl alcohol (128 L) at 50 to 55 °C, concentrating the solution and cooling the residual mass slowly under stirring. The solid thus obtained was filtered, washed with chilled isopropyl alcohol and dried at 40 to 45 °C to give pure Compound H (13.2 Kg, 20.20 moles, purity: 99percent by HPLC).
Example 1; Preparation of amorphous [R- (R*, R* ]- (4-fluorophenvl)-a, 6-dihvdroxv-5- (1-methylethel .-3-phenyl-4- [(phenylamino) carbonyl]-lH-pyrrole-1-heptanoic acid. calcium salt (2: 1) (Atorvastatin Calcium Amorphous); (4R-cis)-1, 1-dimethylethyl-6-{2-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4- [(phenylamino)-carbonyl]-lH-pyrrol-lyllethyl}-2, 2-dimethyl-1, 3-dioxane-4-acetate (Compound H); A mixture of (4R-cis)-1, 1-dimethylethyl-6- (2-aminoethyl)-2, 2-dimethyl-1, 3- dioxane] -4-acetate (9 Kg, 32.96 moles), ()-4-fluoro-a- (2-methyl-l-oxopropyl)-y-oxo- N,-diphenylbenzenebutaneamide (13.33 Kg, 31.93 moles), n-heptane (90 L), tetrahydrofuran (22.5 L), toluene (22.5 L) and pivalic acid (2.18 Kg, 21.30 moles) was heated to reflux temperature for about 40 hrs. The reaction was monitored for completion by HPLC. The reaction mass was cooled and diluted with toluene. The reaction mixture was then washed initially with aqueous sodium hydroxide solution (0.5 N), then with aqueous hydrochloric acid solution (0.5 1V) and followed by brine (10percent). The organic layer was treated with activated carbon, and filtered through a hyflo filter. The organic layer was concentrated to 10percent of the total volume under vacuum. Isopropyl alcohol (34 L) was then added, and the solvent recovered under vacuum, followed by repeated addition of isopropyl alcohol and solvent recovery under vacuum. The residue was dissolved in isopropyl alcohol and de-ionized water (45 L) was added till turbidity appeared. Further de-ionized water (60 L) was added gradually. The precipitated product was filtered, washed with a mixture of isopropyl alcohol and de-ionized water (2: 1) and dried to get the title compound (16.2 Kg, 24.77 moles, 94percent by HPLC). The crude product was purified by dissolving in isopropyl alcohol (128 L) at 50 to 55 °C, concentrating the solution and cooling the residual mass slowly under stirring. The solid thus obtained was filtered, washed with chilled isopropyl alcohol and dried at 40 to 45 °C to give pure Compound H (13.2 Kg, 20.20 moles, purity: 99percent by HPLC).
With Trimethylacetic acid; In tetrahydrofuran; n-heptane; toluene; for 40h;Heating / reflux; A mixture of (4R-cis)-1,1-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane]-4-acetate (9 Kg, 32.96 moles), (+-)-4-fluoro-alpha-(2-methyl-1-oxopropyl)-gamma-oxo-N,beta-diphenylbenzenebutaneamide (13.33 Kg, 31.93 moles), n-heptane (90 L), tetrahydrofuran (22.5 L), toluene (22.5 L) and pivalic acid (2.18 Kg, 21.30 moles) was heated to reflux temperature for about 40 hrs. The reaction was monitored for completion by HPLC. The reaction mass was cooled and diluted with toluene. The reaction mixture was then washed initially with aqueous sodium hydroxide solution (0.5 N), then with aqueous hydrochloric acid solution (0.5 N) and followed by brine (10percent). The organic layer was treated with activated carbon, and filtered through a hyflo filter. The organic layer was concentrated to 10percent of the total volume under vacuum. Isopropyl alcohol (34 L) was then added, and the solvent recovered under vacuum, followed by repeated addition of isopropyl alcohol and solvent recovery under vacuum. The residue was dissolved in isopropyl alcohol and de-ionized water (45 L) was added till turbidity appeared. Further de-ionized water (60 L) was added gradually. The precipitated product was filtered, washed with a mixture of isopropyl alcohol and de-ionized water (2:1) and dried to get the title compound (16.2 Kg, 24.77 moles, 94percent by HPLC). The crude product was purified by dissolving in isopropyl alcohol (128 L) at 50 to 55° C., concentrating the solution and cooling the residual mass slowly under stirring. The solid thus obtained was filtered, washed with chilled isopropyl alcohol and dried at 40 to 45° C. to give pure Compound H (13.2 Kg, 20.20 moles, purity: 99percent by HPLC).
With Trimethylacetic acid; In tetrahydrofuran; n-heptane; toluene; for 40h;Heating / reflux; A mixture of (4R-cis)-1,1-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-1, 3-dioxane]-4-acetate (9 Kg, 32.96 moles), (+/-)- 4-fluoro-alpha-(2-methyl-1-oxopropyl)-gamma-oxoN,beta-diphenylbenzenebutaneamide (13.33 Kg, 31.93 moles), n-heptane (90 L), tetrahydrofuran (22.5 L), toluene (22.5 L) and pivalic acid (2.18 Kg, 21.30 moles) was heated to reflux temperature for about 40 hrs. The reaction was monitored for completion by HPLC. The reaction mass was cooled and diluted with toluene. The reaction mixture was then washed initially with aqueous sodium hydroxide solution (0.5 N), then with aqueous hydrochloric acid solution (0.5 N) and followed by brine (10percent). The organic layer was treated with activated carbon, and filtered through a hyflo filter. The organic layer was concentrated to 10percent of the total volume under vacuum. Isopropyl alcohol (34 L) was then added, and the solvent recovered under vacuum, followed by repeated addition of isopropyl alcohol and solvent recovery under vacuum. The residue was dissolved in isopropyl alcohol and de-ionized water (45 L) was added till turbidity appeared. Further de-ionized water (60 L) was added gradually. The precipitated product was filtered, washed with a mixture of isopropyl alcohol and de-ionized water (2: 1) and dried to get the title compound (16.2 Kg, 24.77 moles, 94percent by HPLC). The crude product was purified by dissolving in isopropyl alcohol (128 L) at 50 to 55 °C, concentrating the solution and cooling the residual mass slowly under stirring. The solid thus obtained was filtered, washed with chilled isopropyl alcohol and dried at 40 to 45 °C to give pure Compound H (13.2 Kg, 20.20 moles, purity: 99percent by HPLC).
With Trimethylacetic acid; In n-heptane; at 100℃; To a mixture of 4-fluoro-a-[2-methyl-l-oxopropyl]-y-oxo-N-P-diphenyl- benzenebutanamide and Cis- 1 , 1 -dimethylethyl-6-(2-aminoethyl)-2,2dimethyl- 1,3- dioxane-4-acetate in heptane, pivalic acid was added over it at 25-35 °C. Reaction mass was heated to reflux (100°C) till completion of reaction. After completion of reaction, heptane was distilled out partially and cooled to 65-75°C. The obtained solution was slowly added to isopropanol contain seeded crystal of compound of formula (II) (form- II) at 0-10°C OR to reaction mass in heptane, isopropanol was added followed by optionally seeded with crystal of compound of formula (II) (form-II) at 40-50°C and gradually cooled to 0-10°C. Product was filtered off, washed with chilled isopropanol and dried under vacuum at 50°C.
65 g With 2,2-dimethylpropanoic anhydride; In 2-methyltetrahydrofuran; at 150℃; for 4h;Autoclave; Inert atmosphere; Green chemistry; 500 mL 2-methyltetrahydrofuran was added to a 1000 mL autoclave. [(4R,6R)-2,2-dimethyl-6-(2-aminoethyl)-[1,3]-dioxan-4-yl-acetic acid tert-butyl ester 27.3 g was added, [5-methyl-4-isopropyl-2-phenyl-1-(4-fluorophenyl)-3-(phenylcarbamoyl)-1,4-hexanedione] 41.7 g, stirring Slowly add 46.5 g of pivalic anhydride, Close the reactor cover and replace the air in the reactor with nitrogen twice. Raise the temperature to 150 °C and react for 4 hours. After the reaction is over, The solvent 2-methyltetrahydrofuran 480 mL was concentrated and concentrated under reduced pressure. And 50.1 g of pivalic acid, A viscous oil was obtained. Add 100ml of water to the oil, 100 mL of isopropanol, warmed to 40 °C, Slowly cool to 20 °C to precipitate a yellow solid, Filtering, Drying to get 65.0 g of atorvastatin intermediate (4R,6R)-6-{2-[5-isopropyl-3-phenyl-2-(4-fluorophenyl)-4-(phenylcarbamoyl)-pyrrol-1-yl-ethyl}-2,2-dimethyl-[1,3]-dioxan-4-yl-acetic acid tert-butyl ester.
With Trimethylacetic acid; In tetrahydrofuran; toluene;Reflux; 9 g of crude ATS-9 (purity 99percent, containing impurities Beta) and atorvastatin mother core M4 were put into a reaction vessel, and 0.5 g of trimethylacetic acid, 100 mL of n-heptane, 30 mL of tetrahydrofuran, and 2 mL of toluene were added. The mixture was heated to reflux with stirring, and the reaction was monitored by HPLC to obtain an atorvastatin calcium condensate, and the content of the impurity A was found to be 0.6percent.
With Trimethylacetic acid; In tetrahydrofuran; n-heptane; for 60h;Reflux; 100 mL of tetrahydrofuran and 100 mL of n-heptane were sequentially added to a 500 mL three-necked flask.10.0 g of ATS-9 and 15 g of B-4, 1.5 g of pivalic acid, and the mixture was heated to reflux for 60 hours. After completion of the reaction by TLC, the mixture was concentrated under reduced pressure, and 30 mL of ethanol was added to the obtained slurry, and the mixture was heated to 50 to 60 ° C to dissolve. The solution is cooled to 8-12 ° C and stirred for 3 hours.Filtration gave a white solid.

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[2]Tetrahedron Letters,1992,vol. 33,p. 2283 - 2284
[3]Patent: WO2004/46105,2004,A2 .Location in patent: Page 36-37
[4]Patent: WO2004/46105,2004,A2 .Location in patent: Page 37
[5]Journal of labelled compounds and radiopharmaceuticals,2000,vol. 43,p. 261 - 270
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[10]Patent: WO2006/97909,2006,A1 .Location in patent: Page/Page column 12
[11]Patent: WO2006/97909,2006,A1 .Location in patent: Page/Page column 11
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  • [ 125971-94-0 ]
  • [ 125971-86-0 ]
YieldReaction ConditionsOperation in experiment
100% With Ra-Ni; ammonia; hydrogen; In methanol; toluene; at 30 - 40℃; under 2625.26 Torr; for 2.5 - 6.5h; A 5-gallon stainless steel reactor was charged with 250 g of Ra-Ni, ((4R,6R)-6-Cyanomethyl-2,2-dimethyl-[1,3]dioxan-4-yl)-acetic acid tert-butyl ester (1.0 kg, 3.71 mol), toluene (6 L), methanol (675 mL), and with 6.5M NH3/MeOH (800 mL). The reactor was sealed, pressure tested to 3.5 bar with N2, and purged 3 times with 3.5 bar of N2. The reactor was purged with H2 to 3.5 bar three times without any agitation. After the reactor was pressurized to 3.5 bar with H2, the reaction stirred for 2-6 h, and a small exotherm to 30 to 40° C. was observed. Stirring was continued until H2 uptake ceased, then the reaction mixture was stirred at 30 to 40° C. for a further 30 min. The mixture was cooled to 20 to 25° C., the H2 source and the agitator were switched off, and the H2 was vented from the reactor. The agitator was switched on and the stainless steel reactor was purged with N2 to 3.5 bar 3 times. Spent Ni catalyst was filtered under a bed of nitrogen, and the stainless steel reactor and spent catalyst bed were washed with toluene (250 mL). The combined filtrates were concentrated to an approximate volume of 500 mL at a maximum temperature of 55° C. under vacuum. [Note: the vacuum was broken with nitrogen]. A saturated sodium chloride solution was added and stirred for 10 minutes under nitrogen. The agitation was stopped and the phases were separated. The lower aqueous layer was discarded, and the organic layer was concentrated to produce the desired product as a yellow oil: (1.054 kg, 104percent, 7percent residual toluene); 1H-NMR (400 MHz, CDCl3): 4.23-4.19 (m, 1H), 3.99-3.95 (m, 1H), 2.74 (t, J=7.1 Hz, 2H), 2.40-2.36 (m, 1H), 2.27-2.22 (m, 1H), 1.58-1.41 (m, 2H), 1.40 (s, 9H), 1.31 (s, 6H), 0.89 (s, 9H); Low resolution mass spectroscopy (APCI) m/z 273 [M+H]+.
99% With ammonia; hydrogen; In methanol; water; at 45℃; under 3750.38 Torr;Sealed tube; Nickel catalyst (Sigma-Aldrich Raney® 2400 Nickel, 0.5 g of 50percent water wet catalyst, 50 wt percent Ni) was weighed into a glass reaction tube and washed three times with methanol. 1 (0.50 g, 1.86 mmol), methanol (4 ml), conc. ammonia aq. (0.1ml) and a magnetic stirrer bar were added and the reaction tube sealed in a pressure vessel. The vessel was purged with hydrogen twice then stirred at 45° C. for 16-20 h under 5 bar hydrogen pressure. Reaction mixture was removed from the catalyst by decantation, washing the catalyst residue twicewith methanol. Combined methanol washings were concentrated under reduced pressure to yield 2 (0.506 g, 99percent). The reaction was analysed by GC-MS which showed a conversion to product of >99percent. For comparison we measured the Ni content in the Ra?Ni catalysed reaction (Table 2) which showed more than ten times the Ni content in the solid, demonstrating the low release of Ni from Ni EnCat.
~ 97% With ammonia; hydrogen;Ra-Ni; In methanol; toluene; at 30 - 40℃; under 2625.26 Torr; for 2.5 - 6.5h; Step E r(4R,6RV6-(2-Amino-ethyl)-2,2-dimethyl-pi ,31dioxan-4-yll-acetic acid tert-butyl ester; A 5-gallon stainless steel reactor was charged with 250 g of Ra-Ni, ((4R,6R)-6-Cyanomethyl-2,2- dimethyl-[1 ,3]dioxan-4-yl)-acetic acid tert-butyl ester (1.0 kg, 3.71 mol), toluene (6 L), methanol (675 mL), and with 6.5M NH3ZMeOH (800 mL). The reactor was sealed, pressure tested to 3.5 bar with N2, and purged 3 times with 3.5 bar of N2. The reactor was purged with H2 to 3.5 bar three times without any agitation. After the reactor was pressurized to 3.5 bar with H2, the reaction stirred for 2-6 h, and a small exotherm to 30 to 40 0C was observed. Stirring was continued until H2 uptake ceased, then the reaction mixture was stirred at 30 to 40 0C for a further 30 min. The mixture was cooled to 20 to 25 0C, the H2 source and the agitator were switched off, and the H2 was vented from the reactor. The agitator was switched on and the stainless steel reactor was purged with N2 to 3.5 bar 3 times. Spent Ni catalyst was filtered under a bed of nitrogen, and the stainless steel reactor and spent catalyst bed were washed with toluene (250 mL). The combined filtrates were concentrated to an approximate volume of 500 mL at a maximum temperature of 55 0C under vacuum. [Note: the vacuum was broken with nitrogen]. A saturated sodium chloride solution was added and stirred for 10 minutes under nitrogen. The agitation was stopped and the phases were separated. The lower aqueous layer was discarded, and the organic layer was concentrated to produce the desired product as a yellow oil: (1.054 kg, 104percent, -7percent residual <n="19"/>toluene); 1H-NMR (400 MHz, CDCI3): 4.23-4.19 (m, 1H), 3.99-3.95 (m, 1 H), 2.74 (t, J=7.1 Hz, 2H), 2.40- 2.36 (m, 1H), 2.27-2.22 (m, 1H), 1.58-1.41 (m, 2H), 1.40 (s, 9H), 1.31 (s, 6H), 0.89 (s, 9H); Low resolution mass spectroscopy (APCI) m/z 273 [M+Hf.
97.6% With ammonia; hydrogen; In methanol; at 45℃; under 9120.61 - 11400.8 Torr; for 6h; To a 250 ml autoclave was added 4.0 g (15 mmol) of 2 - ((4R, 6R) -6-cyanomethyl-2,2-dimethyl-1,3-dioxan-4-yl) Acetic acid tert-butyl ester (prepared in Example 8)80 grams of saturated ammonia methanol solution,1.0Craney Nickel,Nitrogen replacement 2 times,Through the hydrogen (pressure of about 12-15 atmospheres),The temperature was raised to 45 ° C for 6 hours.Reaction is completed,Cooled to 20 ° C,filter,Recovery solvent,To the residue was added 20 g of acetone dissolved,Through the dry hydrogen chloride gas until the solid thoroughly precipitated,filter,The filter cake was added to 30 g of dichloromethane and 30 g of a 5percent sodium bicarbonate mixture,Stirring at 20 ° C for 1 hour,Layered,The aqueous layer was extracted twice with dichloromethane (10 g each)The dichloromethane layer was combined and the solvent was recovered to give 4.0 g of 2 - ((4R, 6R) -6-aminoethyl-2,2-dimethyl-1,3-dioxane-4- Yl) acetic acid tert-butyl ester,Purity 99.4percent (HPLC),Yield 97.6percent.
97.5% With ammonia; hydrogen; In methanol; at 30 - 40℃; under 2250.23 - 3000.3 Torr; for 6h;Autoclave; Add 100 mL of methanol, 10.0 g of ATS-8, and 0.8 g of Raney nickel to a 1 L autoclave.After stirring and dissolving, the ammonia gas is introduced into the kettle, and after the passage is completed, hydrogen is supplied to the kettle.The pressure in the autoclave was kept at 0.3 to 0.4 MPa, and the temperature in the autoclave was controlled at 30 to 40 °C.The hydrogen passing time was 6 hours, and after completion of the reaction, it was filtered under pressure to a concentrator and concentrated under reduced pressure to give 9.9 g of oily material ATS-9, yield 97.5percent.
91% With palladium 10% on activated carbon; hydrogen; acetic acid; at 20 - 30℃; for 8h; In the reaction kettle, first add compound VI (5g), acetic acid 50ml, and then add 10percent palladium carbon (0.5g) acetic acid solution.(5 ml), hydrogenation at 20-30 ° C for 8 h. After completion of the reaction, the celite was filtered, and the filtrate was evaporated to give an oil. The oil was dissolved in 30 ml of water and the pH was adjusted to 8-9 with liquid ammonia and then extracted with dichloromethane. Separating the dichloromethane layer and using anhydrous sulfurThe sodium salt was dried and evaporated to give compound I (4.62 g, 91percent).
With ammonia;nickel; In methanol; water; at 0 - 40℃; under 2206.72 - 2574.5 Torr; for 6 - 8h; 75 ml of methanol was charged into a hydrogenation vessel at 0-5°C. 15 grams of Raney nickel was washed under a nitrogen atmosphere with 100 ml of water and added to the hydrogenation vessel at the same temperature. 14.3 ml of aqueous 15-18percent ammonia was added, then 20.0 grams of (4R,Cis)-1 ,1- dimethylethyl-6-(2-cyano)-2,2-dimethyl-1 ,3-dioxane-4-acetate was dissolved in 45 ml of methanol and added to the vessel. The vessel was maintained under a hydrogen pressure of 3 to 3.5 Kg/cm2 at 30-400C for 6-8 hours. After completion of the reaction, the reaction mass was filtered through a flux calcined diatomaceous earth bed and washed with 36 ml of methanol. The solvent was distilled from the filtrate under vacuum at temperatures below 6O0C, then 52 ml of methanol were added and again the solvent was distilled, and this was repeated two additional times with 52 ml portions of methanol. Finally, the solvent was distilled completely to produce 18 +/- 2 grams of the title compound having a moisture content by the Karl Fischer method not more than about 5percent by weight and a purity of at least about 95percent by high performance liquid chromatography.
With ammonia; hydrogen;nickel; In water; isopropyl alcohol; under 2585.81 Torr;Product distribution / selectivity; Example 1: (Comparative)50 g tert-butyl isopropylidene (TBIN), prepared as described in Tetrahedron Letters, 1992, 2279, 13.25 g wet sponge nickel catalyst, 28percent ammonia solution (137.5 ml) and 375 ml isopropyl alcohol (IPA) are added to a pressure vessel. The mixture is reduced with 50 psi of hydrogen, then filtered and concentrated in vacuo. The resulting oil is dissolved in 250 ml warm toluene, water washed and again concentrated in vacuo to give an amino ester. The amino ester, 85 g 4-fluoro-alpha-(2- methyl-l-oxopropyl)-gamma-oxo-N,beta-diphenyl-benzenebutanamide (diketone of atorvastatin), 12.5 g pivalic acid, 137.5 ml tetrahydrofuran (THF) and 137.5 ml hexanes are charged to an argon inerted pressure vessel which is sealed and heated to 750C for 96 hours. After cooling the solution is diluted with 400 ml methyl tert- butyl ether (MTBE) and washed firstly with dilute aqueous sodium hydroxide followed by dilute aqueous hydrochloric acid. The mixture is then concentrated in vacuo to give an acetonide ester.The acetonide ester is dissolved in 275 ml warm methanol and aqueous hydrochloric acid (5 g of 37percent hydrochloric acid in 75 ml of water) is added. The mixture is stirred at 300C to produce a diol ester. 100 ml methyl tert-butyl ether and aqueous sodium hydroxide (150 ml of H2O and 25 g of 50percent aqueous sodium hydroxide) are then added and the mixture stirred at 3O0C to produce a sodium salt. 600 ml water is added and the mixture washed twice with 437.5 ml methyl tert-butyl ether. Residual methyl tert-butyl ether and some methanol is removed from the aqueous layer by atmospheric distillation to a temperature of 87-9O0C. The mixture is stirred at 75-850C for 18 hours, then cooled, acidified and extracted into 875 ml toluene. The mixture is heated at reflux for 4 hours and water is removed azeotropically. After cooling, the mixture is filtered and washed with toluene. The crude lactone is then recrystallised from toluene and lactone is isolated as an white solid.Yield: 36 g ; 59.8percent from tert-butyl isopropylidene. Impurity level: crude Methyl ester 1.3 percent. pure Methyl ester 0.6 percent.; Example 2 50 g tert-butyl isopropylidene (TBIN), prepared as described in Tetrahedron Letters,1992, 2279, 13.25 g wet sponge nickel catalyst, 28percent ammonia solution (137.5 ml) and 375 ml isopropyl alcohol (IPA) are added to a pressure vessel. The mixture is reduced with 50 psi of hydrogen, then filtered and concentrated in vacuo. The resulting oil is dissolved in 250 ml warm toluene, water washed and again concentrated in vacuo to give an amino ester. The amino ester, 85 g 4-fluoro-alpha-(2- methyl-l-oxopropyl)-gamma-oxo-N,beta-diphenyl-benzenebutanamide (diketone of atorvastatin prepared by a method disclosed in United States Patent Number 5,155,251 which is herein incorporated by reference and Bauman K.L, Butler D.E., Deering C.F., et al Tetrahedron Letters 1992;33:2283-2284), 12.5 g pivalic acid, 137.5 ml tetrahydrofuran (THF) and 137.5 ml hexanes are charged to an argon inerted pressure vessel which is sealed and heated to 750C for 96 hours. After cooling the solution is diluted with 400 ml methyl tert-butyl ether (MTBE) and washed firstly with dilute aqueous sodium hydroxide followed by dilute aqueous EPO <DP n="9"/>hydrochloric acid. The mixture is then concentrated in vacuo to give an acetonide ester.The acetonide ester is dissolved in 275 ml warm methanol and aqueous hydrochloric acid (5 g of 37percent hydrochloric acid in 75 ml of water) is added. The mixture is stirred at 3O0C to produce a diol ester. 100 ml methyl tert-butyl ether and aqueous sodium hydroxide (150 ml of H2O and 25 g of 50percent aqueous sodium hydroxide) are then added and the mixture stirred at 3O0C to produce a sodium salt. 600 ml water is added and the mixture washed twice with 437.5 ml methyl tert-butyl ether.In this case, the mixture is distilled under atmospheric pressure to a batch temperature of 70-750C. A vacuum of approximately -0.25 bar is then applied and distillation is continued until the methanol content of the mixture is reduced to less than 2.6percentw/v. The batch is stirred at 75-85°C for 18 hours, then cooled, acidified and extracted into 875 ml toluene. The mixture is heated at reflux for 4 hours and water removed azeotropically. After cooling the mixture is filtered, washed with toluene and dried directly. Lactone is isolated as awhite solid.Yield: 37.9 g ; 63percent from tert-butyl isopropylidene. Impurity level : Methyl ester 0.16percent.; Example 3 50 g tert-butyl isopropylidene (TBIN), prepared as described in Tetrahedron Letters, 1992, 2279, 13.25 g wet sponge nickel catalyst, 28percent ammonia solution (137.5 ml) and 375 ml isopropyl alcohol (IPA) are added to a pressure vessel. The mixture is reduced with 50 psi of hydrogen, then filtered and concentrated in vacuo. The resulting oil is dissolved in 250 ml warm toluene, water washed and again concentrated in vacuo to give an amino ester. ...
With ammonia; hydrogen;nickel; In methanol; at 20℃; under 3310.08 - 3677.86 Torr; for 4 - 12h; (4R-cis)-1,1-Dimethylethyl-[6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate (Compound F) Pure (4R-cis)-1,1-dimethylethyl-[6-cyanomethyl-2,2-dimethyl-1,3-dioxan]-4-acetate (Compound E) dissolved in ammonia saturated methanol is hydrogenated in the presence of activated Raney nickel by applying hydrogen pressure of 4.5 to 5 kg/cm2 at room temperature under stirring for 4 to 12 hours. The reaction is monitored for completion by gas chromatography. The catalyst is filtered through hyflo bed and concentrated to recover methanol completely under reduced pressure to get the title compound.
With ammonia; hydrogen; nickel; In methanol; at 20℃; under 3310.08 - 3677.86 Torr; for 4 - 12h; (4R-cis)-I, I-Dimethylethyl- [6- (2-aminoethyl)-2, 2-dimethyl-1, 3-dioxan-4-yi] acetate (Compound F); Pure (4R-cis)-1, 1-dimethylethyl- [6-cyanomethyl-2, 2-dimethyl-1, 3-dioxan] -4-acetate (Compound E) dissolved in ammonia saturated methanol is hydrogenated in the presence of activated Raney nickel by applying hydrogen pressure of 4.5 to 5 kg/cm2 at room temperature under stirring for 4 to 12 hours. The reaction is monitored for completion by gas chromatography. The catalyst is filtered through hyflo bed and concentrated to recover methanol completely under reduced pressure to get the title compound.
With ammonia; hydrogen;Raney nickel; In methanol; at 20℃; under 3310.08 - 3677.86 Torr; for 4 - 12h; Pure (4R-cis)-1,1-dimethylethyl-[6-cyanomethyl-2,2-dimethyl-1,3-dioxan]-4-acetate (Compound E) dissolved in ammonia saturated methanol is hydrogenated in the presence of activated Raney nickel by applying hydrogen pressure of 4.5 to 5 kg/cm2 at room temperature under stirring for 4 to 12 hours. The reaction is monitored for completion by gas chromatography. The catalyst is filtered through hyflo bed and concentrated to recover methanol completely under reduced pressure to get the title compound.
With ammonia; hydrogen;Raney nickel; In methanol; at 20℃; under 3310.08 - 3677.86 Torr; for 4 - 12h; Pure (4R-cis)-1,1-dimethylethyl-[6-cyanomethyl-2,2-dimethyl-1,3-dioxan]-4-acetate (Compound E) dissolved in ammonia saturated methanol is hydrogenated in the presence of activated Raney nickel by applying hydrogen pressure of 4.5 to 5 kg/cm2 at room temperature under stirring for 4 to 12 hours. The reaction is monitored for completion by gas chromatography. The catalyst is filtered through hyflo bed and concentrated to recover methanol completely under reduced pressure to get the title compound.

  • 3
  • [ 125971-86-0 ]
  • [ 887355-33-1 ]
  • [ 265989-39-7 ]
YieldReaction ConditionsOperation in experiment
With Trimethylacetic acid; In cyclohexane; at 25 - 90℃; for 50h; A mixture of cyclohexane (500 ml) and (4R-cis)-1,1-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate (52.2 gms) were stirred for 10 minutes at 25-30°C. N-(2-(benzyloxy)phenyl)-2-(2-(4-fluorophenyl)-2-oxo- 1 -phenylethyl)-4-methyl-3-oxopentanamide(100 gms) was added to the reaction mixture at 25-30°C and stirred for 10 minutes at thesame temperature. Pivalic acid (9.8 gms) was added to the reaction mixture. Heated thereaction mixture to 85-90°C and stirred for 40 hours at the same temperature. Cooled the reaction mixture to 55°C and distilled off the. solvent completely under reduced pressure and cooled to 25-30°C. Dichloromethane (1000 ml) was added to the obtained compound at 25- 30°C and stirred for 20 minutes at the same temperature. Purified water (200 ml) was addedto the reaction mixture at 25-30°C and stirred for 20 minutes at the same temperature. Both the organic and aqueous layers were separated and organic layer was washed with 5percent aqueous sodium bicarbonate solution. Organic layer was dried over sodium sulfate. Distilled off the solvent completely from the organic layer under reduced pressure below 45°C to get the title compound
  • 4
  • [ 125971-86-0 ]
  • [ 163217-67-2 ]
  • [ 163217-68-3 ]
  • 5
  • [ 682356-88-3 ]
  • [ 125971-86-0 ]
YieldReaction ConditionsOperation in experiment
87% With water; triphenylphosphine; In tetrahydrofuran; at 50℃; for 2h; To a solution of azide (52.1 mg, 0.174 mmol) in a mixture of THF (1.0 mL) and water (0.1 mL), triphenylphosphine (91.3 mg, 0.348 mmol) was added and the resulting mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated to remove THF, followed by coevaporation with toluene two times. The crude residue was purified by flash chromatography (CH2Cl2/MeOH/Et3N, 95:4:1) to give amine 15 as colorless oil (41.2 mg, 87percent). Colorless oil; IR (neat) nu 3374, 2981, 2938, 2873, 1731, 1176 cm-1; 1H NMR (CDCl3) delta 4.25-4.19 (m, 1H), 3.98-3.92 (m, 1H), 2.80-2.77 (m, 2H), 2.39 (dd, J=6.9, 15.1 Hz, 1H), 2.26 (dd, J=6.2, 15.1 Hz, 1H), 1.95 (br s, 2H), 1.64-1.50 (m, 3H), 1.42 (s, 9H), 1.42 (s, 3H), 1.33 (s, 3H), 1.30-1.15 (m, 1H); 13C NMR (CDCl3) delta 170.2, 98.6, 80.5, 67.4, 66.2, 42.6, 39.5, 38.4, 36.5, 30.1, 28.0, 19.7; [alpha]D22 +11.5 (c 0.28, CHCl3); ESI-MS m/z 274.2 [M+H]+; HRMS (ESI) Anal. Calcd forC14H28NO4 m/z 274.2013 [M+H]+, found; 274.2015.
87% With water; triphenylphosphine; In tetrahydrofuran; at 50℃; for 2h; The compound I (52.1 mg, 0.174 mmol, 1 equivalent), THF (1.0 mL), distilled water (0.10 mL), and triphenylphosphine (91.3 mg, 0.348 mmol, 2 equivalents) were put in a 10 mL test tube, and the resulting mixture was stirred at 50°C for two hours. THF was then distilled away under reduced pressure. To the residue thus obtained, toluene (5 mL) was added, and the resulting mixture was concentrated under reduced pressure. Water contained in the residue was distilled away as an azeotropic mixture. To the residue thus obtained, toluene (5 mL) was added again and the resulting mixture was concentrated under reduced pressure. The residue thus obtained was purified by flash column chromatography (methylene chloride/methanol/triethylamine = 95/4/1 (volume ratio)) to obtain a compound J (tert-butyl [(4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate) as a colorless oily matter. Yield 41.2mg (87percent).
85% With palladium on activated charcoal; hydrogen; In methanol; for 3h; The formula (10) 10. tert-butyl2 - (6 - (2-azidoethyl) - 2,2-dimethyl-1,3-dioxan-4-yl) acetat 4.94 g by adding into the containing 10 ml of dry methanol 20 ml round-bottom flask, palladium carbon added 290 mg. Continuous access hydrogen, 3 hours after the completely disappear under TLC detection of raw materials, diatomaceous earth filter the palladium-carbon, the filtrate after concentrating under reduced pressure to obtain the final product yellow oily liquid 3.83g, yield 85percent
  • 6
  • [ 125971-86-0 ]
  • 7-amino-3(R),5(R)-dihydroxyheptanoic acid ter-butyl ester hydrochloride salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; In tetrahydrofuran; water; at 20℃; for 3.5h; To a 1 L reactor equipped with a mechanical stirrer, a thermometer and a condenser, was added THF (384 g) and (4R-CIS)-6- (2-AMINOETHYL)-2, 2-DIMETHYL-1, 3-dioxane-4-acetic acid tert-butyl ester 16 (109 g, 0.4 mol). A solution of 37percent aq. HC1 (38 g) was added dropwise over about 30 mins at room temperature. Addition of the acid lowered the pH from 10 TO 3. The acidic solution was stirred at room temperature for 3 hours. The solvent was stripped on a rotary evaporator at 20 mm Hg vacuum at 50°C. The residue (112 g, quant. ) was dissolved in THF (335 g) and dried over molecular sieves (33 g). Drying over molecular seives lowered the amount of water FROM-2percent to 0.8percent.
  • 7
  • [ 805242-34-6 ]
  • [ 125971-86-0 ]
  • [ 805242-35-7 ]
YieldReaction ConditionsOperation in experiment
74% With Trimethylacetic acid; In tetrahydrofuran; n-heptane; toluene; for 22 - 25h;Heating / reflux; To a solution of Formula XIII (4.62 mmoles) in heptane:toluene:tetrahydrofuran (4:1:1) was added a compound of Formula IX (6.99 mmoles) and pivalic acid (4.768 mmoles). The mixture was refluxed with azeotropic removal of water for 22 to 25 hours. The reaction mixture was concentrated, ethyl acetate was added, washed with sodium bicarbonate solution and brine, dried over anhydrous sodium sulphate and concentrated to give the crude product. The crude product was purified on column (silica gel, 100-200 mesh) using 7percent ethyl acetate in hexane. 1H NMR(CDCl3, 300 MHz): delta 0.99-1.08 (m, 2H), 1.25 (s, 3H), 1.34 (s), 1.43 (s, 9H), 1.96 (d, J=6Hz, 6H), 1.58-1.63 (m, 2H), 2.21 (dd, J=158.6Hz, 1H), 2.37 (dd, J=15 9Hz, 1H), 3.51 (sept, J=6Hz), 3.65 (brs, 1H), 3.75-3.85 (m, 1H), 4.00-4.25 (m, 2H), 5.03 (s, 2H), 6.83-7.25 (m, 14H). MS (+ve ion mode): m/z 670 (M++1). yield 74percent
With Trimethylacetic acid; In tetrahydrofuran; n-heptane; toluene; for 22 - 25h;Heating / reflux; Example 3: Preparation of 1-f2-(6-tert-butoxycarbonylmethyl-2,2-dimethyl-f 1,31dioxan-4- yl)-ethyll-5-(4-fluorophenyl)-2-isopropyl-4-phenyl- l H-pyrrole-3-carboxylic acid benzyl ester of Formula VI; To a solution of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo- pentanoic acid benzyl ester Formula IV (4.62 mmles) in heptane: toluene: tetrahydrofuran (4:1:1), <strong>[125971-86-0]tert-butyl [(4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate</strong> of Formula V (6.99 mmoles) and pivalic acid (4.768 mmoles) were added. The mixture was refluxed with azeotropic removal of water for about 22 to 25 hours. The reaction mixture was concentrated and ethyl acetate was added. It was washed with sodium bicarbonate solution and brine, dried over anhydrous sodium sulphate and concentrated to give crude product. The crude product was purified on column (silica gel, 100-200 mesh) using 7percent ethyl acetate in hexane.
  • 8
  • [ 71783-54-5 ]
  • [ 125971-86-0 ]
  • [ 845280-54-8 ]
YieldReaction ConditionsOperation in experiment
95% With triethylamine; In acetonitrile; at 20℃; A solution of [(4R,6R)-6-(2-Amino-ethyl)-2,2-dimethyl-[1,3]dioxan-4-yl]-acetic acid tert-butyl ester (26.3 g; 96 mmol) and bromo-(4-fluoro-phenyl)-acetic acid methyl ester (22.6 g; 92 mmol) in acetonitrile (200 mL) was treated with triethylamine (18.5 g; 182 mmol). After 30 minutes a considerable precipitate was noted. The reaction was allowed to stir at rt overnight then filtered to remove the precipitate. The filtrate was concentrated to dryness. The residue was dissolved in EtOAc, washed with H2O and brine, dried (MgSO4), and concentrated to give a crude oil. The oil was triturated with hexanes to give a white solid which was collected by vacuum filtration and air dried; yield: 38.1 g (95percent); Low resolution mass spectroscopy (APCI) m/z 440 [M+H]+.
With triethylamine; In acetonitrile; at 20℃; for 16h; Example 5; To a dry MEOH solution (50 ML) containing 4-FLUOROPHENYLACETIC acid 5A (5 g, 0.0324 mole) was added a catalytic amount of 4-toluene sulfonicacid (0.324 mmole, 61 mg). The solution was refluxed for 4 h. The resultant solution was concentrated under reduced pressure to give pale-yellow syrup. The material was diluted with EtOAc (100 mL), and neutralized with NAHCO3 (1M, 5 mL). The organic layer was then washed with H20 (10 mLx2), followed by brine (10 mL), dried over MGS04 and filtered. The filtrate was concentrated to give a pale-yellow liquid. (5.33 g, 31.75 mmole, 98 percent, MS M+H = 169 found: 169, 1H NMR structure confirmed). The methyl ester (2. 0g, 11.9 mmole) was then added to a CCL4 solution (100 mL) containing NBS (2.33 g, 13.09 mmole). The reaction mixture was refluxed at 80 °C for 3 h to yield the brominated methyl ester 5b. The cooled solution was filtered through a pad of silica gel to remove excess SUCCINIMIDE, the filtrate was evaporated under reduced pressure, and the resultant material was transferred to the next reaction without further purification. To an acetonitrile solution containing the amine (TBIA, 2.44 g (8.94 mmole) /15 mL ACN) was added the compound 5B (ca. 2 g). While the reaction mixture was stirred triethylamine was added dropwise (1.70 ML, 12.2 mmole 1.5 equiv. ). The reaction mixture was stirred at ambient temperature for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and diluted with EtOAc (25 mL). The organic layer was treated with H2O, dried over MGS04, and filtered. The filtrate was then concentrated under reduced pressure to give the compound 5c, 3.29 g. Isobutyryl chloride (0.53 ML, 4.99 mmole in 5 mL DCM) was added dropwise to a chilled DCM solution (10 mL) containing the compound 5C (2.0 g, 4.54 mmole). While the reaction mixture was stirred, a triethylamine solution (1.27 ML, 2 equiv. in 5 mL DCM) was added dropwise. The reaction mixture was agitated as it was warmed to room temperature for 2 h. After completion of the reaction, the reaction mixture was treated with IN HCL (20 mL), followed by sat. NAHC03 (3 mL). The organic layer was then washed with water and brine, dried over MGS04, and filtered. The filtrate was concentrated under reduced pressure to give pale-yellow syrup. This was purified by a column chromatography using a gradient of EtOAc-Hexane mixture (from 0 to 25 percent of EtOAc). The isolated yield of the methyl ester was 2.10 g, 4.13 mmole, 90.9 percent. The methyl ester (250 mg, 0.50 mmole) was dissolved in a LIOH solution (1M, THF : water (5: 1) mixture), and vigorously stirred for 3 h. The reaction mixture was neutralized to pH 7 by titrating it with 1N HCL solution. The desired product was then extracted with EtOAc (20 mL). The organic layer was washed with H2O and brine, dried over MgS04, and filtered. The filtrate was then evaporated under reduced pressure to give a white amorphous material 5 (200 mg, 0.40 mmole, 80 percent, MS M+H = 496 found: 496, LU NMR structure confirmed).; Intermediate 3; Solution of 44.87 g (0.164 mol) of amine (TBIA) in 180 ml of acetonitrile was treated with a solution of 36.89 g (0.149 mol) of intermediate 2 in 90 ml of acetonitrile. Mixture was treated with 31.2 ml (0.224 mol) of triethylamine dropwise and stirred overnight at room temperature. Reaction was concentrated and the residue taken up in ethyl acetate and washed with water (2x). Organics were dried over sodium sulfate, filtered, and concentrated to yield approximately 69 g of a thick oil. MS APCI+ 440.2 (M+1).
  • 9
  • [ 125971-86-0 ]
  • [ 76585-78-9 ]
  • [ 845281-66-5 ]
YieldReaction ConditionsOperation in experiment
Example 31; Step A; The chiral amine, starting material A, and the A-KETOESTER, starting material B, were combined in 150 ml of DCE. After stirring RT for 1 h, solid sodium triacetoxyborohydride ("NaBH (OAc) 3") was added and the resulting mixture was allowed to stir RT for 48 h. The reaction mixture was quenched with sat. aqueous NHLICI (10 mL) and water (200 mL). The aqueous layer was adjusted to pH > 10 with KOH. The organic layer was diluted with dichloromethane, removed, washed with brine, dried (NA2SO4), and concentrated to a crude yellow oil. TLC indicates several major components including starting amine and starting ketone as well as the desired product [Rf = 0.48, Hexanes/ethyl acetate (1: 1), KMN04)], and reduced ketoester [RF = 0.67, Hexanes/ethyl acetate (1 : 1), KMN04)] This material was purified by silica gel chromatography eluting with a gradient of hexanes/ethyl acetate mixture [Hexanes/ethyl acetate (95: 5 to 70: 30) ] to give 3.85 g of the desired product, C, as a light oil. A Loop LC-MS [M+H] + = 464 H NMR is consistent with expected product that appears to be contaminated with benzyl ALCOHOL ~ 1 equiv The resulting material, C will be used in next reaction without additional purification.
  • 10
  • [ 867308-95-0 ]
  • [ 125971-86-0 ]
  • [ 867308-96-1 ]
YieldReaction ConditionsOperation in experiment
21% With toluene-4-sulfonic acid; benzoic acid; In n-heptane; for 65h;Heating / reflux; A mixture of 3-Cyclopropyl-2-(4-fluoro-benzoylamino)-3-oxo-propionic acid benzyl ester (6.0 g, 17 mmol), [(4R,6R)-6-(2-Amino-ethyl)-2,2-dimethyl-[1,3]dioxan-4-yl]-acetic acid tert-butyl ester (TBIA) (9.2 g, 33.8 mmol), benzoic acid (6.19 g, 50.7 mmol), and p-toluenesulfonic acid (0.29 g, 1.7 mmol) in n-heptane (150 mL) was heated to reflux for 65 h with the removal of water (Dean-Stark trap). The reaction mixture was cooled, diluted with EtOAc (100 mL), and washed with 1M NaOH (2*150 mL) and sat NH4Cl, dried (Na2SO4) and concentrated to a yellow-brown oil. Purification by flash chromatography [SiO2, Ethyl Acetate/hexanes 10-50percent] provides the desired product as a yellow glass that was dried under high vacuum. Yield: 2.1 g (21percent); Low resolution mass spectroscopy (APCI) m/z 593 [M+H]+; Anal. Calcd. For C34H41F1N2O6: C, 68.90; H, 6.97; N, 4.73. Found: C, 68.66; H, 7.01; N, 4.64.
21% With benzoic acid;toluene-4-sulfonic acid; In n-heptane; for 65h;Heating / reflux; Step B; 1-[2-((4R,6R)-6-tert-Butoxycarbonylmethyl-2,2-dimethyl-[1.3]dioxan-4-yl)-ethyl]-2-(4-fluoro-phenyl)-5-cyclopropyl-1H-imidazole-4-carboxylic acid benzyl ester; A mixture of 3-Cyclopropyl-2-(4-fluoro-benzoylamino)-3-oxo-propionic acid benzyl ester (6.0 g, 17 mmol), [(4R,6R)-6-(2-Amino-ethyl)-2,2-dimethyl-[1,3]dioxan-4-yl]-acetic acid tert-butyl ester (TBIA) (9.2 g, 33.8 mmol), benzoic acid (6.19 g, 50.7 mmol), and p-toluenesulfonic acid (0.29 g, 1.7 mmol) in n-heptane (150 mL) was heated to reflux for 65 h with the removal of water (Dean-Stark trap). The reaction mixture was cooled, diluted with EtOAc (100 mL), and washed with 1M NaOH (2.x.150 mL) and sat NH4Cl, dried (Na2SO4) and concentrated to a yellow-brown oil. Purification by flash chromatography [SiO2, Ethyl Acetate/hexanes 10-50percent] provides the desired product as a yellow glass that was dried under high vacuum. Yield: 2.1 g (21percent); Low resolution mass spectroscopy (APCI) m/z 593 [M+H]+; Anal. Calcd. For C34H41F1N2O6: C, 68.90; H, 6.97; N, 4.73. Found: C, 68.66; H, 7.01; N, 4.64.
  • 11
  • 2-(4-fluoro-phenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-5-isopropyl-1H-imidazole-4-carboxylic acid [ No CAS ]
  • [ 125971-86-0 ]
  • 1-[2-(6-tert-butoxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl)-ethyl]-2-(4-fluorophenyl)-5-isopropyl-1H-imidazole-4-carboxylic acid benzyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
55.69% With acetic acid;toluene-4-sulfonic acid; In xylene; at 50℃; for 24h;Heating / reflux; A solution of 2-(4-Fluoro-benzoylamino)-4-methyl-3-oxo-pentenoic acid benzyl ester (1.50 g, 4.5 mmole), TBIA (1.5 equiv.), and acetic acid (glacial, 1.20 mL) acid in xylenes was warmed to 50° C. and treated with catalytic p-toluenesulfonic acid. The reaction mixture was heated to reflux for 24 h using a Dean-Stark trap charged with Na2SO4. The reaction mixture was cooled and concentrated under reduced pressure to give a light-brown amorphous residue. This material was taken up in EtOAc (25 mL), washed with 1M HCl, NaHCO3, water, and brine, dried (MgSO4), and concentrated under reduced pressure to give an amorphous material. Purification by flash chromatography (SiO2, EtOAc/hexanes 0-20percent) gave the above named compound as a tan glass; Yield: 1.39 g (55.69percent); Low resolution mass spectroscopy (APCI) m/z 595 [M+H]+.
  • 12
  • [ 867309-02-2 ]
  • [ 125971-86-0 ]
  • [ 867308-86-9 ]
YieldReaction ConditionsOperation in experiment
With benzoic acid; In n-heptane; at 99℃; for 14h; Step F; 2-(4-Fluoro-phenvpi-1-r2-((2R.4R)-4-hvdroxy-6-oxo-tetrahvdro-pyran-2-yl)-psithvpi-5-isoDropyl-1H-imidazole- 4-carboxylic acid benzylamide; To a 2-L 3-necked, round-bottomed flask outfitted with a mechanical stirrer, a J-KEM/heating mantle setup, and a Dean-Stark trap (with condenser) was charged a mixture of lambda/-(1-Benzylcarbamoyl-3- methyl-2-oxo-butyl)-4-fluorobenzamide (123.0 g, 345.1 mmol), benzoic acid (63.0 g, 517.5 mmol, 1.5 equiv.), and heptane (700 mL). This slurry was treated with [(4R,6R)-6-(2-Amino-ethyl)-2,2-dimethyl- [1 ,3]dioxan-4-yl]-acetic acid tert-butyl ester (119.4 g, 414.0 mmol, 1.2 equiv.). The reactor was purged with nitrogen, then heated to reflux (approximately 99 °C) over 14 h in order to azeotropically remove the water formed during the reaction. After 14 h, a small amount of starting material remained by TLC (1 :1 " heptane:ethyl acetate). A small portion of TBIA (5.0 g, 18.0 mmol, 0.06 equiv) was added to the reactor, and the mixture was stirred at reflux for another 2 h, after which time TLC showed no more starting material remaining. The reactor was cooled to 30 0C, and the contents were fully dissolved with ethyl acetate (600 mL), washed with saturated sodium bicarbonate solution (2 x 400 mL), washed with 10percent aqueous sodium chloride, then concentrated in vacuo to provide 400.1 g of a very thick orange oily solid. This solid was taken up into MeOH (600 mL) while heating to 40 0C (difficult to dissolve). The solution was charged with a premixed solution of concentrated HCI (136 g) in water (400 mL), and the remaining solution was heated back to 40 0C and held at this temperature for over 2 h. The walls of the reactor were washed down with MeOH (20 mL) and TLC after an additional 1 h showed mainly diol terf-butyl ester. To the reaction mixture was added MTBE (500 mL), followed by slow addition (-10 min) of a pre-mixed solution of NaOH (110 g) in water (200 mL). The pH of the mixture at this point was 13.0, and the pot temperature rose to almost 50 0C. The reaction was stirred and slowly cooled to 23 0C over 2 h, after which time TLC (6:1 ethyl acetate:heptane) showed that all fert-butyl ester was consumed (only baseline remaining). The mixture was diluted with more MTBE (1 L) and water (500 mL), and was phase separated. The bottom aqueous product-containing layer was extracted again with MTBE (500 mL) and set aside. The combined MTBE layers were vigorously washed with 5percent NaOH solution (200 mL), then discarded. The combined aqueous extracts were combined and distilled down to approximately 1/2 volume on the rotary evaporator using full vacuum at 700C (CAUTION. Severe bumping was possible; use large round-bottom flask and a bump-trap for this concentration). The mixture was then stirred at 23 0C and treated with 6N HCI (200 mL, added over 1 min), at which point the mixture turned cloudy. The pH of this suspension was 7.0 (pH was measured with pH meter). To this mixture was added ethyl acetate (800 mL), and the mixture was stirred vigorously. The mixture was then treated with 6N HCI until pH of the aqueous layer (phase-cut; lower layer) was 5.5. In total, additional 6N HCI (75 mL) was added to achieve this pH. The layers were separated and the top organic layer was set aside. The aqueous <n="20"/>layer was extracted with ethyl acetate (200 ml_) and then discarded. The combined organics were washed with water and then concentrated in vacuo to give 175 g of an orange oil that foamed slightly under vacuum. To this mixture was added 1percent HCI (1 ml.) and toluene (900 mL), and the reaction mixture was heated to reflux under a Dean-Stark trap for 2.5 h [Note: Not completely in solution until near reflux]. TLC showed clean conversion to lactone. The reaction mixture was cooled to 30 0C, and toluene was removed by rotary evaporator to give 171 g of a brown oil that solidified while under vacuum for 2 h. This solid was taken up in dichloromethane (60 mL) and the solution was added to the top of a 900 g silica gel column that was pre-packed in 4:1 ethyl acetate/heptane. A solution of 4:1 ethyl acetate/heptane (4 L) eluted initially a purple impurity of high Rf (0.8), followed by elution of lactone cleanly by ramping eventually to neat ethyl acetate over another 12 L. Additional ethyl acetate (6 L) was charged until the product was completely eluted as indicated by TLC (5:1 ethyl acetate/heptane). Fractions 3-6 (500 mL each) contained the purple impurity, and fractions 10-22 were combined and concentrated to afford 103.5 g of a dark grey oil that formed a tan foamy residue while drying under vacuum. NMR of this residue showed contamination with benzoic acid, so this crude product was re-dissolved in ethyl acetate (500 mL), washed with saturated sodium bicarbonate solution (2 x 200 mL), followed by washing with 100 mL water. The organic solvent was concentrated in vacuo to yield the desired product as a pale tan foamy amorphous solid: (88.4 g 53percent over 4 combined...
  • 13
  • [ 936756-72-8 ]
  • [ 125971-86-0 ]
  • [ 936756-73-9 ]
YieldReaction ConditionsOperation in experiment
34.6% With Trimethylacetic acid; In tetrahydrofuran; n-heptane; toluene;Heating / reflux; Example 4: Preparation of r(4R,6R)-6-f2-{2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4- (tetrahydropyran-2-yloxy methyl) phenyl amino)carbnoyl]pyrrol-l-yl|ethylV2,2-dimethyl- [L31dioxan-4-yl1-acetic acid tert-butyl ester; A mixture of 2-[2-(4-fluorophenyl)-2-oxo-l-phenylethyl]-4-methyl-3-oxo-pentanoic acid [4~(tetrahydropyran-2-yloxy methyl)phenyl] amide (2.0 g, 0.004 mol, 1 equiv.), an amine of Formula IX (1.5 g, 0.006 mol, 1.5 equiv.), pivalic acid (0.45 mL, 0.004 mol, 1.03 equiv.), and heptane:toluene:tetrahydrofuran (4: 1 : 1 , 24 ml) was placed in a round bottom flask equipped with a Dean-Stark setup. The reaction mixture was refluxed at with azeotropic removal of water. After the completion of reaction (TLC monitoring), the solvents were removed on a rotary evaporator. The residue was diluted with ethyl acetate and a saturated solution of sodium bicarbonate was added to this solution. The aqueous layer was extracted with ethyl acetate and <n="12"/>the organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated. The crude mixture was purified on column (silica gel, 100-200 mesh, 15percent ethyl acetate/hexane) to obtain the pure product. Yield: 1.0 g (34.6percent).MS (+ion mode): m /z 769.45 (M+ 1); 1HNMR (CDCl3, 300Hz): delta 0.9-1. l(m, 2H); 1.30(s, IH), 1.36(s, 3H); 1.43(s, 9H); 1.50-1.77(m,14 6H); 2.20-2.40(m, 2H); 3.52-3.70(m, 3H); 3.85-3.89(m, 2H); 4.05-4.25(m, 2H); 4.40(d, J=12 Hz,lH);4.64-4.70(m, 2H); 6.86-7.25(m, 14H).
34.6% With Trimethylacetic acid; In tetrahydrofuran; n-heptane; toluene;Heating / reflux; Example 4 Preparation of [(4R,6R)-6-(2-{2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(tetrahydropyran-2-yloxy methyl)phenyl amino)carbonyl]pyrrol-1-yl}ethyl)-2,2-dimethyl-[1,3]dioxan-4-yl]-acetic acid tert-butyl ester A mixture of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-pentanoic acid [4-(tetrahydropyran-2-yloxy methyl)phenyl]amide (2.0 g, 0.004 mol, 1 equiv.), an amine of Formula IX (1.5 g, 0.006 mol, 1.5 equiv.), pivalic acid (0.45 mL, 0.004 mol, 1.03 equiv.), and heptane:toluene:tetrahydrofuran (4:1:1, 24 ml) was placed in a round bottom flask equipped with a Dean-Stark setup. The reaction mixture was refluxed at with azeotropic removal of water. After the completion of reaction (TLC monitoring), the solvents were removed on a rotary evaporator. The residue was diluted with ethyl acetate and a saturated solution of sodium bicarbonate was added to this solution. The aqueous layer was extracted with ethyl acetate and the organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated. The crude mixture was purified on column (silica gel, 100-200 mesh, 15percent ethyl acetate/hexane) to obtain the pure product. Yield: 1.0 g (34.6percent). MS (+ion mode): m/z 769.45 (M+1); 1H NMR (CDCl3, 300 Hz): delta 0.9-1.1 (m, 2H); 1.30 (s, 1H), 1.36 (s, 3H); 1.43 (s, 9H); 1.50-1.77 (m, 14 6H); 2.20-2.40 (m, 2H); 3.52-3.70 (m, 3H); 3.85-3.89 (m, 2H); 4.05-4.25 (m, 2H); 4.40 (d, J=12 Hz, 1H); 4.64-4.70 (m, 2H); 6.86-7.25 (m, 14H).
  • 14
  • [ 936847-61-9 ]
  • [ 125971-86-0 ]
  • [ 805241-61-6 ]
YieldReaction ConditionsOperation in experiment
With Trimethylacetic acid; In tetrahydrofuran; n-heptane; toluene; for 28 - 35h;Heating / reflux; Example 4: Preparation of Methyl 4-((ri-(2-r(4/g.6/?V6-(2-tert-butoxy-2-oxoethylV2.2- dimethyl-l,3-dioxan-4-yllethvU-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-lH-pyrrol-3- yl"|carbonyl|amino)benzoate of Formula VIII ; Pivalic acid (44.2 g, 0.433 moles) was added to a mixture of a compound ofFormula VI (200 g, 0.421 moles) and [6-(2-Amino-ethyl)-2,2-dimethyl-[l,3-dioxan-4-yl]- acetic acid .pound.-butyl ester of Formula VII (137.9 g, 0.505 moles) in solvent system of heptane, toluene and tetrahydrofuran in the ratio of 4: 1 : 1 (2.52 L). The reaction mixture was refluxed for about 28 to about 35 hours. The reaction mixture was cooled to about 0° C and stirred till the product precipitates. The precipitated product was filtered and washed with hexanes (1 L). The solid was dried under vacuum (lOmbar) at about 50 0C to obtain the desired product.Yield: 210 g (1.05, w/w); LCMS: m/z (M+ 1) 713.2; Melting range: 158.8 - 159.5° C; 1H NMR (CDCl3): delta 1.03-1.06 (m, IH^NCH2CH2-), 1.30-1.36 (2xs,6H, >C(CH3)2 m,lH,>NCH2CH2- merged together), 1.43 (s,9H, -C(CHs)3), 1.52-1.54 (d,6H, -CH(CH3)2), 1.66(m,2H,C-5 -CH2-), 2.2-2.4 (m,2H,-CH2COOlBu), 3.6 (m,lH, -CH(CH3)2), 3.7(m,lH,C-4 >CHO-), 3.85 (8,3H5-OCH3), 3.85 (m,lH,C-6 >CHO-), 4.1 (m,2H,>NCH2-), 6.97-7.85 (m,14H,Ar-H and -NH).
  • 15
  • [ 1331869-19-2 ]
  • [ 125971-86-0 ]
  • [ 125971-95-1 ]
YieldReaction ConditionsOperation in experiment
79% With 1,8-diazabicyclo[5.4.0]undec-7-ene; Trimethylacetic acid; In cyclohexane; at 80 - 84℃; for 25h;Dean-Stark; Reflux; A mixture of Diketone intermediate 11(100 g), amino ketal intermediate III (68 g) and pivalic acid (9.1 g) in cyclohexane (450mL) was refluxed (80-84°C) in a Dean-Stalk apparatus, with azeotropic removal of water. A solution of DBU (13 g) in cyclohexane (50 mL) was added over a period of 60 mm and the reaction mass maintained at mild reflux for 24h when HPLC analysis revealed completion of the reaction. The reaction mass was gradually cooled to 55-65°C and washed with hot (55-65°C) water (500 mL), while maintain temperature above 55°C. Mild vacuum was applied and the solvent was completely distilled off, while maintaining temperature below 65°C. Isopropyl alcohol (100 mL) was added to the residue, stirred for 10- 30 mm and the solvent again completely distilled off under vacuum while maintaining temperature below 65°C. Isopropyl alcohol (650 mL) was added to the residue and thetemperature of the mixture was raised to 80-84°C and maintained at the same temperature till the material completely dissolved. Gradually cooled the reaction mixture to 40-46°C, seeded with ?1 g of compound IV and further cooled the reaction mixture to 25-35°C. The mixture was stirred for another 60-90 mm and then DM water (500 mL) was added at 25-35°C, over a period of 60-90 mm. The reaction mixture was slurred for lhr at 25-35°C, further cooled to 9-15°C, stirred for another 3-4 h and filtered. The reaction vessel was rinsed with chilled (0-5°C) mixture of IPA (80 mL) & water (20 mL) and the wet cake washed with it. The material was dried for 15-60 mm under suction.The above semi-dried material was dissolved in IPA (500 mL) at 80-84°C, gradually cooled to25-35°C over a period of 2-3h. The reaction mass was slurred, at 25-35°C, for 30-60 mm, further cooled to 0-6°C and maintained for 3-4 h at the same temperature. The precipitated material was washed with chilled (0-5°C) IPA (50 mL) and dried under vacuum at 54-60°C for 12 h to obtain compound of formula IV as off-white solid material (125g, 79percent yield).HPLC purity: 99.5percent, Impurity IVa: 0.20percent.
With Trimethylacetic acid; In tetrahydrofuran; hexane; toluene; at 110℃; for 30h;Inert atmosphere; A mixture of amine 15 (40.2 mg, 0.147 mmol), diketone 16 (55.8 mg, 0.133 mmol), pivalic acid (12.0 mg, 0.118 mmol) in n-hexane/toluene/THF=1:4:1 (0.48 mL) was heated at 110 °C for 30 h under Ar. After cooling to room temperature, the mixture was diluted with AcOEt and washed with satd NaHCO3 aq, then dried over Na2SO4. The resulting residue after evaporation was dissolved in THF (0.5 mL). To the solution was added 2 N HCl in MeOH (1 mL) at 0 °C and the resulting solution was stirred at room temperature for 30 min. The mixture was diluted with CH2Cl2, and resulting biphasic mixture was separated. Organic layer was washed with satd NaHCO3 aq and brine, then dried over Na2SO4. The filtrate was concentrated under reduced pressure and the resulting residue was dissolved in wet THF (0.2 mL). 1 N NaOH aq (2 mL) was added at 0 °C and the resulting solution was stirred at room temperature for 6 h. The mixture was diluted with CH2Cl2 and 1N HCl aq. The resulting biphasic mixture was extracted with CH2Cl2. The combined organic layers were washed with brine, then dried over Na2SO4. Volatiles were removed under reduced pressure and the resulting solid residue was purified by flash chromatography (CH2Cl2/MeOH 18/1) on silica gel to give atorvastatin as a colorless solid. (54.8 mg, 67percent over three steps).
  • 16
  • C91H116N18O17 [ No CAS ]
  • [ 125971-86-0 ]
  • C101H133N17O21 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; Compound 344 (0.014 mmol, 25 mg), tert-butyl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (0.021 mmol, 5.82 mg), HATU (0.043 mmol, 16.18 mg) and Hunig's Base (0.071 mmol, 0.012 ml) in DMF (1.5 mL) were combined in a reaction vial. The reaction mixture was stirred overnight at rt. The solution was poured into EtOAc and washed with 0.5N HCl. The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was dissolved in CH2C12 (0.8 mL), TFA (0.8 mL) and H20 (0.2 mL). The mixture was stirred overnight at rt and concentrated in vacuo. The resulting residue was purified by reverse phase preparative HPLC (Column: Phen-Luna Axia CI 8 5 u 30 x 100 mm; Solvent A: 95 H2O/5 MeCN/0.05 TFA; Solvent B: 95 MeCN/ 5 H2O/0.05 TFA; 5percent-100percent gradient in 15 min) to afford 1044 (2.49 mg, 8percent) as a white solid. MS (ESI+) rt 0.72 min, m/z 1646.3.
  • 17
  • C22H29NO6 [ No CAS ]
  • [ 125971-86-0 ]
YieldReaction ConditionsOperation in experiment
85% With hydrazine hydrate; In ethanol; at 60℃; for 1h; The compound O (45 mg, 0.11 mmol, 1 equivalent) was dissolved in ethanol (2.5 mL), and hydrazine monohydrate (70 mL, 2.25 mmol, 20 equivalents) was added, followed by stirring at 60°C for one hour. After bringing the resulting reaction solution to room temperature, the precipitated solids were filtered off and the filtrate was concentrated under reduced pressure. To the residue, methylene chloride and saturated brine were added, and the resulting aqueous layer was extracted with methylene chloride. The resulting organic layer was dried over anhydrous sodium sulphate. After filtration and concentration, the residue thus obtained was purified by flash column chromatography (methylene chloride/methanol/triethylamine = 95/4/1 (volume ratio)) to obtain a compound J as a colorless oily matter. Yield 25.5 mg (85percent).
  • 18
  • tert-butyl 2-((4R,6R)-6-(-2-oxime-ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate [ No CAS ]
  • [ 125971-86-0 ]
YieldReaction ConditionsOperation in experiment
88% With ammonia; hydrogen; In methanol; at 50℃; under 11251.1 Torr; for 5h;Autoclave; 4.7 tert-Butyl ((4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate 3 A stainless steel autoclave was charged with 12 (1.00 g, 3.5 mmol), Raney Ni (0.50 g) and satd NH3 in methanol (20 mL). The reactor was sealed and purged with H2 3 times, then pressurized to 15 bar with H2 and stirred at 50 °C for 5 h. The reaction mixture was cooled to rt, filtered, and concentrated in vacuo to afford 3 (0.95 g, 100percent) as a clear viscous oil with a relative content of 95percent (GC areapercent), which was pure enough for the synthesis of atorvastatin. Pure 3 (0.84 g, 88percent) was isolated by flash chromatography (dichloromethane/MeOH/Et3N, 100:5:0.1). [alpha]D14 = +16.9 (c 0.34, CHCl3) {Lit. 5 [alpha]D20 = +13.12; Lit. 7 [alpha]D22 = +11.5 (c 0.28, CHCl3)}. 1H NMR (400 MHz, CDCl3): delta = 4.24-4.27 (m, 1H), 3.95-4.02 (m, 1H), 3.26 (br, 2H), 2.89 (m, 2H), 2.42 (dd, J = 15.2, 7.2 Hz, 1H), 2.29 (dd, J = 15.2, 6.0 Hz 1H) 1.62-1.74 (m, 2H), 1.51-1.58 (m, 1H), 1.45 (s, 3H), 1.44 (s, 9H), 1.36 (s, 3H), 1.21-1.29 (m, 1H). 13C NMR (100 MHz, CDCl3): delta = 170.2, 98.8, 80.6, 67.7, 66.1, 42.6, 38.3, 38.1, 36.4, 30.1, 28.1, 19.7. MS (EI): m/z = 274 [M+H]+, 258 [M-CH3]+.
  • 19
  • C91H114N16O18 [ No CAS ]
  • [ 125971-86-0 ]
  • C107H141N17O22 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; N,N-dimethyl-formamide; at 20℃; Compound N of Example 1 (26.3 mg, 0.015 mmol) and tert-butyl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (4.18 mg, 0.015 mmol) in CH2Cl2 (1 mL) was treated with a solution of 0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (8.72 mg, 0.023 mmol) and N-ethyl-N-isopropylpropan-2-amine (5.33 muL, 0.031 mmol) in DMF (100 mul) at rt overnight. The reaction mixture was quenched with H2O (0.5 mL) and 1N HCl (0.5 mL). The mixture was extracted with CH2Cl2 (2*), and the combined organics were dried over MgSO4, filtered, and concentrated in vacuo. The resulting yellow oil was dissolved in MeOH (0.5 mL) and THF (0.5 mL) and treated with 2 M LiOH (22.94 muL, 0.046 mmol). The solution was acidified with 1N HCl (0.25 mL), washed with brine (0.5 mL), and extracted with CH2Cl2 (3*). The combined organics were dried over MgSO4, filtered and concentrated to a solid. The residue was dissolved in CH2Cl2 (1 mL) and TFA (1 mL) at rt, monitored for conversion by LCMS, and upon completion the solvent was removed. The resulting crude oil was purified by reverse phase prep HPLC (C18 30*100 mm, Phenominex Luna) to afford Example 13 (12.1 mg) as a white solid. MS (ESI+) rt 0.71 min, m/z 833.2 (M+2). HPLC Purity: Phenomenex Luna 5u C18(2) 150*4.6, 10-100percent B, 20 min gradient, 1 mL/min flow rate (rt 13.28 min, 95percent); mobile A (0.1percent TFA H2O), mobile B (0.1percent TFA MeCN).
  • 20
  • [ 1446358-48-0 ]
  • [ 125971-86-0 ]
  • C31H36F2N6O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
90% With triethylamine; In 1,4-dioxane; water; at 60℃; for 2h; A mixture containing 3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-l-(2-fluorobenzyl)- -lH-pyrazol-5-yl)isoxazole (Intermediate-1A, 364 mg, 1.0 equiv.), (4R,6R)-tert-butyl-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxane-4-acetate (3.0 equiv.) and triethylamine (3.0 equiv.) in 1,4-Dioxane (3.7 ml) and water (1.3 ml) was heated to 60 °C for 2 h. The mixture was diluted in ethyl acetate (50 ml) and washed with water (50 ml). The organic layer was dried, filtered and evaporated in vacuo to give a crude oil. The oil was purified by column chromatography using a 0 to 50percent ethyl acetate/hexanes gradient to give the desired compound as a white solid (536 mg, 90percent yield). NMR (500 MHz, CHLOROFORM-i/) delta ppm 8.34 (s, 1 H) 7.97 (s, 1 H) 7.23 (s, 1 H) 7.01 - 7.08 (m, 1 H) 6.86 - 6.91 (m, 1 H) 6.83 (t, 1 H) 6.72 (t, 1 H) 6.46 (s, 1 H) 5.87 (s, 2 H) 4.00 (qd, 2 H) 3.73 - 3.82 (m, 1 H) 3.46 - 3.54 (m, 1 H) 2.29 - 2.36 (m, 1 H) 2.18 - 2.25 (m, 1 H) 1.64 - 1.81 (m, 2 H) 1.43 - 1.52 (m, 2 H) 1.30 - 1.37 (m, 15 H).
  • 21
  • [ 125971-86-0 ]
  • [ 125971-96-2 ]
  • (4R-cis)-6-[2-[2-isopropyl-4-phenyl-3-benzoylamino-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxan-4-acetic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
1015 g 20L to clean and dry the kettle cyclohexane 13L, under nitrogen, were put 800g (4R-Cis) -2,2- dimethyl-6- (2-aminoethyl) -1,3-bis oxygen six ring 4-acetic acid tert-butyl1040g2- [2- (4- fluorophenyl) -2-oxo-1-phenylethyl] -4-methyl-3-oxo -N- phenylpentaneamide, the nitrogen system was maintained state, was stirred at room temperature for 30 minutes; 160g was added to the kettle pivalic acid, through the steam heating, the system was under reflux, held at reflux until the reaction was complete stirring was continued state, not higher than 80 evaporated to dryness under reduced pressure, the residue was added 3L isopropanol, evaporated to dryness under reduced pressure, 2L of isopropyl alcohol was added, stirred for 2 hours at room temperature, cooled to 5-10 , filtered, and the filter cake was rinsed with 2L of isopropyl alcohol, drained under reduced pressure, the filter cake at 60 and dried in vacuo 4 hours to give 1015g (4R-cis) -6- [2- [2- isopropyl-3-phenyl-4-anilino-methyl-5- (4-fluorophenyl) -1H - pyrrol-1-yl] ethyl] -2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester solid.
  • 22
  • [ 125971-86-0 ]
  • [ 501121-34-2 ]
  • 23
  • tert-butyl 2-[(4R,6S)-2,2-dimethyl-6-(2-nitroethenyl)-1,3-dioxan-4-yl]acetate [ No CAS ]
  • [ 125971-86-0 ]
YieldReaction ConditionsOperation in experiment
25 g With palladium 10% on activated carbon; hydrogen; In methanol; at 60℃; under 2250.23 Torr; for 2h;Autoclave; n a 500 mL autoclave, 2- ((4R, 6S) -6- (2-nitroethylene) -2,2-dimethyl-1,3-dioxane-4-yl) acetic acid tert-butyl ester (30 g, 0. 1 mol) and palladium carbon catalyst (10percent palladium content) were added to 200 mL of methanol, and the inside of the autoclave was replaced with nitrogen three times, and then the inside of the autoclave 3 times, through the hydrogen, control the pressure inside the autoclave 0.3MPa, and gradually heated to 60 ° C, in this condition to the reaction of hydrogen pressure does not decline, continue to maintain the reaction 2h, the reaction of raw materials through the test, and then the kettle material The temperature was cooled to room temperature, the pressure inside the kettle was vented, the autoclave was opened, the product was poured into a funnel for filtration, the kettle was washed twice with methanol 10 mL, the filtrate was poured into a three-necked flask, The product is washed in a three-necked bottle, the product is filtered off, washed with a small amount of water, the wet cake is placed on the surface dish, and dried to give 2- ((4R, 6R) _6_ (2-aminoethyl) -2,2-dimethyl-1,3-dioxane] 4- {4'-yl) acetic acid tert-butyl ester 25g
  • 24
  • [ 125971-86-0 ]
  • [ 78-84-2 ]
  • C18H33NO4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With magnetron; In tetrahydrofuran; at 20℃;Inert atmosphere; Molecular sieve; Under the protection of nitrogen,First, 1.73 g of isobutyraldehyde was sequentially used in a syringe.(4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid tert-butyl ester 5.46 g,Tetrahydrofuran 15ml,Add 5g of 3A molecular sieve,100ml of magnetronIn a two-necked flask,Stir at room temperature for 12-24h;Then filtering the molecular sieve in the above reaction solution,Under the protection of nitrogen,The filtrate was slowly added dropwise with a syringe to 3.17 g of p-fluorobenzoyl chloride.Potassium carbonate 3.31g,10 ml of a tetrahydrofuran in a 100 ml two-necked flask (with a stirring magnet)And keep stirring,After the addition,After reacting for 1 h at room temperature,1.66 g of t-butyl isocyanide was added dropwise to the reaction solution with a syringe.And keep stirring,After the addition,After reacting for 1 h at room temperature,After adding 3.31 g of potassium carbonate,4.42 g of 3-phenylpropynylaniline was added dropwise to the reaction solution with a syringe.And keep stirring,After the addition, the room temperature was reacted for 24 hours.After the reaction is completed,Extracted with ethyl acetate,Washed,dry,The residue was concentrated by column chromatography eluting with ethyl acetate: petroleum ether (V ethyl acetate: V dichloromethane = 1:4)get(4R-cis)-6-[2-[2-(4-Fluorophenyl)-5-(1-isopropyl)-3-phenyl-4-[(phenylamino)carboxy]-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-Tert-butyl acetatePure product 9.17-9.55 g,The yield is 72-75percent.
  • 25
  • [ 125971-86-0 ]
  • [ 1173184-84-3 ]
YieldReaction ConditionsOperation in experiment
16.9% With acetic acid; sodium nitrite; In water; at 20℃; for 4.5h;Cooling with ice; tert-Butyl 2-((4R, 6/i)-6-(2-aminoethyl)-2,2-dimethyl- 1 ,3 -dioxan-4-yl (acetate (10 g, 36.6 mmol) was dissolved in 200 mL of 4: 1 H20: AcOH and the mixture was placed in ice bath. To this mixture was slowly added aqueous sodium nitrite (150 mL, 2 M) via a syringe pump over 30 min. The reaction was stirred for 4 h at room temperature. TLC showed the reaction was complete. The reaction was extracted with EtOAc (3c50 mL). The organic layer was dried with anhydrous MgS04, filtered, and the filtrate was concentrated via rotary evaporation. The residue was purified by flash chromatography (silica gel, 1 % ~ 10% ethyl acetate in petroleum ether) to give tert-butyl 2-((4f?,6/?)-6-(2-hydroxyethyl)-2,2-dimethyl-l,3-dioxan-4- yl)acetate (1.7 g, 16.9 %) as a colorless oil.
  • 26
  • [ 75-89-8 ]
  • [ 125971-86-0 ]
  • tert-butyl 2-((4R,6R)-2,2-dimethyl-6-(2-(2,2,2-trifluoroacetamido)ethyl)-1,3-dioxan-4-yl)acetate [ No CAS ]
  • 27
  • N-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-2-(2-(4-fluorophenyl)-2-oxo-1-phenylethyl)-4-methyl-3-oxopentanamide [ No CAS ]
  • [ 125971-86-0 ]
  • tert-butyl 2-((4R,6R)-6-(2-(3-((4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)carbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
52% With Trimethylacetic acid; In tetrahydrofuran; n-heptane; toluene; at 90℃; for 20.5h; Obtained in Example 10 N- (4-(((tert-butyldimethylsilyl) oxy) methyl) phenyl) -2- (2- (4-fluorophenyl) -2-oxo-1-phenylethyl) -4-methyl-3- Oxopentanamide(258 mg) was dissolved in heptane / THF / toluene (6 ml / 1.5 ml / 1.5 ml),tert-butyl 2-((4R, 6R) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxan-4-yl) acetate(190 mg, 0.69 mmol) and pivalic acid (47 mg, 0.46 mmol) were added and heated at 90 C. for 20.5 hours. After cooling to room temperature, the reaction solution is diluted with EA, followed by saturated aqueous NaHCO3 solution,Brine, washed with distilled water.The extracted organic layer was dried with Na 2 SO 4 and filtered under reduced pressure.The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound.190 mg (52% yield) of a yellow solid;
  • 28
  • 2-(2-(4-fluorophenyl)-2-oxo-1-phenylethyl)-N-(4-(((4-methoxybenzyl)oxy)methyl)phenyl)-4-methyl-3-oxopentanamide [ No CAS ]
  • [ 125971-86-0 ]
  • tert-butyl 2-((4R,6R)-6-(2- (2-(4-fluorophenyl)-5-isopropyl-4-((4-(((4-methoxybenzyl)oxy)methyl)phenyl)carbamoyl)-3-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
40% With Trimethylacetic acid; In tetrahydrofuran; n-heptane; toluene; at 95℃; for 32h; Example 112- (2- (4-fluorophenyl) -2-oxo-1-phenylethyl) -N- (4-(((4-methoxybenzyl) oxy) methyl) phenyl) -4-methyl- obtained in 3-oxopentanamide(630 mg, 1.11 mmol) was diluted in heptane / THF / toluene (16 ml / 4 ml / 3 ml),Stir at room temperature.Pivalic acid (170 mg, 1.66 mmol) was dissolved in the reaction solution.tert-butyl 2-((4R, 6R) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxan-4-yl) acetate (455 mg, 1.66 mmol) was dissolved in toluene (1 diluted in ml),It was added dropwise to the reaction solution.next, The reaction solution was refluxed at 95 C. for 32 hours,After diluting the obtained reaction solution with EA, NaHCO 3 (aq) and distilled water,Washed several times with brine.The extracted organic layer was dried with MgSO 4 and filtered under reduced pressure.The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound.Light yellow oil 350 mg (yield 40%);
  • 29
  • 2-(2-(4-fluorophenyl)-2-oxo-1-phenylethyl)-N-(4-(hydroxymethyl)phenyl)-4-methyl-3-oxopentanamide [ No CAS ]
  • [ 125971-86-0 ]
  • [ 805241-63-8 ]
YieldReaction ConditionsOperation in experiment
70% With Trimethylacetic acid; In tetrahydrofuran; n-heptane; toluene;Dean-Stark; 2- (2- (4-fluorophenyl) -2-oxo-1-phenylethyl) -N- (4- (hydroxymethyl) phenyl) -4-methyl-3-oxopentanamide (obtained in step 1) 140 g, 1 eq) tert-butyl 2-((4R, 6R) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxan-4-yl) acetate (128 g, 1.5 eq)And pivalic acid (33 g, 1.03 eq) were added to a mixed solvent of heptane / toluene / THF (1.18 L / 0.42 L / 0.42 L).The reaction solution was refluxed overnight under a Dean-Stark trap to remove water. After cooling the reaction solution to 20 concentrated under reduced pressure,CH 2 Cl 2 (1.4 L) was added to the concentrate, followed by stirring. The CH2Cl2 layer was washed twice with distilled water (0.7 L).The CH 2 Cl 2 layer was concentrated under reduced pressure, IPA (1.86 L) was added thereto, and the mixture was stirred until it dissolved cleanly.The reaction solution was further stirred at 60 to 65 C. for 1 hour. Distilled water (0.56 L) was added thereto, the mixture was cooled to 20 to 30 C., and then stirred at 20 to 30 C. for 2 hours and 0 to 5 C. for 1 hour to form a solid.The resulting solid was filtered, washed with IPA (0.14 L) and distilled water (0.14 L) and vacuum dried at 50-55 C. for 12 hours to afford the title compound.150 g (70%) solid;
  • 30
  • [ 2600636-58-4 ]
  • [ 125995-13-3 ]
  • [ 2600636-59-5 ]
YieldReaction ConditionsOperation in experiment
60% With Trimethylacetic acid In tetrahydrofuran; n-heptane; toluene Inert atmosphere; Reflux; Pivalic acid (0.5 g, 4.9 mmol, 3.77 equiv.) was added, under nitrogen atmosphere, to a solution ofthe previously synthesized phenylpentanamide derivative (4, 1 g, 1.3 mmol, 1.00 equiv.) and tert-butyl2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (5, 1 g, 3.7 mmol, 2.85 equiv.) intoluene:heptane:tetrahydrofuran (1:4:1 v/v) (20 mL). The reaction mixture was refluxed for 24 h withazeotropic removal of water, monitored by TLC, cooled to room temperature, and extracted withethyl acetate (3 x50 mL). The organic phase was washed with saturated aqueous sodium chloridesolution (50 mL). The solvent was removed under vacuum, the desired Bpin labeling precursor (6)was obtained as a pale yellow solid in approximately 60% yield (0.6 g, 0.8 mmol) after purification bycolumn chromatography (petroleum ether:ethyl acetate). 4.2. Characterization Datatert-butyl 2-((4R,6R)-6-(2-(2-isopropyl-4-phenyl-3-(phenylcarbamoyl)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (Bpin labeling precursor 6):1H NMR (500 MHz, CDCl3) δ7.72 (d, J = 7.9 Hz, 2 H), 7.20-7.15 (m, 9 H), 7.06 (d, J = 7.9 Hz, 2 H), 6.97(t, J = 7.4 Hz, 1 H), 6.88 (s, 1 H), 4.17-4.07 (m, 2 H), 3.91-3.82 (m, 1 H), 3.67-3.57 (m, 2 H), 2.35 (dd,J = 15.2, 7.3 Hz, 1 H), 2.22 (dd, J = 15.2, 5.8 Hz, 1 H), 1.72-1.58 (m, 2 H), 1.53 (dd, J = 7.1, 3.9 Hz, 6 H),1.43 (s, 9 H), 1.34 (d, J = 2.6 Hz, 9 H), and 1.23 (s, 9 H).13C NMR (126 MHz, CDCl3)δ 184.5, 170.3, 164.9, 141.8, 138.4, 135.1, 134.7, 134.6, 130.6, 130.6, 129.9,128.6, 128.3, 126.5, 123.5, 121.7, 119.6, 115.4, 98.7, 83.9, 80.7, 66.4, 65.9, 42.5, 40.9, 38.5, 38.0, 35.9, 29.9,28.1, 27.0, 26.0, 24.9, 24.5, 21.7, 21.6, and 19.7.HRMS-ESI: m/z calcd. for C46H60BN2O7 [M + H]+ 763.452, found 763.379.
  • 31
  • [ 2376189-97-6 ]
  • [ 125995-13-3 ]
  • [ 2376189-27-2 ]
YieldReaction ConditionsOperation in experiment
58% With tris[2-phenylpyridinato-C2,N]iridium(III); tetrakis(acetonitrile)copper(I)tetrafluoroborate; potassium carbonate In acetonitrile at 15℃; for 2.5h; Inert atmosphere; Irradiation; Aniline 22 Under ambient atmosphere, a 4 ml. glass-vial was charged with thianthrenium salt TT-22(165 mg, 0.299 mmol, 1.00 equiv.), [Cu(MeCN)4]BF4(94 mg, 0.30 mmol, 1 .0 equiv.), Ir(ppy)3(10 mg, 15 pmol, 5.1 mol%), K2C03(83 mg, 0.60 mmol, 2.0 equiv.), and acetonitrile (1 .5 ml_, c = 0.20 M). Tert-butyl 2-((4F?,6F?)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3-dioxan-4-yl)acetate (123 mg, 0.450 mmol, 1.50 equiv.) was added, and the suspension was degassed by bubbling through argon with a cannula for 5 min. While stirring, the suspension was irradiated for 2.5 h at 15 °C using a blue LED (60 W). The suspension was added to an aqueous saturated NaHC03solution (20 mL), and the aqueous phase was extracted with DCM (3 x 20 mL). The organic phase was dried over MgS0 , and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel eluting with hexanes / EtOAc (1 :0-7:3 (v/v)) to afford 91 mg (58%) of 22 as brown oil.R/ = 0.34 (hexanes / EtOAc, 8:2 (v/v)).NMR Spectroscopy:1H NMR (500 MHz, CDCI3, 25 °C, d): 7.38 - 7.32 (m, 2H), 6.90 - 6.84 (m, 2H), 6.82 - 6.76 (m, 2H), 6.61 - 6.54 (m, 2H), 4.31 - 4.22 (m, 1 H), 4.08 - 3.99 (m, 2H), 3.29 - 3.14 (m, 2H), 2.44 (dd, J = 15.2, 6.9 Hz, 1 H), 2.31 (dd, J = 15.2, 6.2 Hz, 1 H), 1.78 (q, J = 6.3 Hz, 2H), 1 .60 - 1 .54 (m, 1 H), 1 .46 (s, 3H), 1 .45 (s, 9H), 1 .40 (s, 3H), 1 .32 - 1.25 (m, 1 H).13C NMR {1H} (126 MHz, CDCI3, 25 °C, d): 170.4, 158.6, 147.0, 145.7, 132.5, 121 .4,1 18.8, 1 14.2, 1 13.8, 98.9, 80.8, 68.2, 66.3, 42.8, 41 .4, 36.5, 35.7, 30.3, 28.2, 19.9.HRMS-ESI (m/z) calc’d. for C26H35N05Br+[M + H]+, 520.169324; found, 520.169660; deviation: 0.65 ppm.
58% With tris[2-phenylpyridinato-C2,N]iridium(III); tetrakis(acetonitrile)copper(I)tetrafluoroborate; potassium carbonate In acetonitrile at 15℃; for 2.5h; Inert atmosphere; Irradiation;
  • 32
  • [ CAS Unavailable ]
  • [ 125995-13-3 ]
  • [ 2376189-26-1 ]
YieldReaction ConditionsOperation in experiment
53% With tris[2-phenylpyridinato-C2,N]iridium(III); tetrakis(acetonitrile)copper(I)tetrafluoroborate; potassium carbonate In acetonitrile at 15℃; for 1.3h; Inert atmosphere; Irradiation;
  • 33
  • [ 2497486-23-2 ]
  • [ 125995-13-3 ]
  • [ 2497486-24-3 ]
YieldReaction ConditionsOperation in experiment
53.33% With Trimethylacetic acid In toluene at 110℃; for 12h; 9.4 Step 4: Synthesis of tert-butyl 2-[(4R,6R)-6-[2-[2-(2-benzyloxy-4-fluoro-phenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxan-4-yl]acetate (5) 2-[2-(2-Benzyloxy-4-fluoro-phenyl)-2-oxo-1-phenyl-ethyl]-4-methyl-3-oxo-N-phenyl-pentanamide(0.529 g, 1.01 mmol) in toluene (5 mL) and tert-butyl 2-[(4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate (414.29 mg, 1.52 mmol) was added PIVALIC ACID (123.82 mg, 1.21 mmol, 139.28 uL) to the solution. The reaction mixture was heated to 110° C. for 12 hours. The starting material was consumed and the desired mass (57%) was detected according to LCMS. The reaction mixture was quenched with saturated NaHCO3 solution (60 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine (60 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (PE/EtOAc = 60/1 to 8/1) to give the title compound (0.41 g, 538.81 umol, 53.33% yield) as a yellow oil.
  • 34
  • tert-butyl [(4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate [ No CAS ]
  • [ 102-08-9 ]
  • C27H37N3O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
84% With C15H12N4O3; potassium carbonate In ethanol; water at 20℃; for 20h; Irradiation;
  • 35
  • [ 125995-13-3 ]
  • [ 98-59-9 ]
  • [ 2191449-14-4 ]
YieldReaction ConditionsOperation in experiment
70% With triethylamine In dichloromethane at 20℃; Inert atmosphere; Cooling with ice;
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