Structure of 5-Oxorosuvastatin methyl ester
CAS No.: 147118-39-6
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CAS No. : | 147118-39-6 |
Formula : | C23H28FN3O6S |
M.W : | 493.55 |
SMILES Code : | O=C(OC)C[C@H](O)CC(/C=C/C1=C(C(C)C)N=C(N(C)S(=O)(C)=O)N=C1C2=CC=C(F)C=C2)=O |
MDL No. : | MFCD12755726 |
InChI Key : | ULUNETUXUVEFLH-DOJUMQAQSA-N |
Pubchem ID : | 22848603 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 34 |
Num. arom. heavy atoms | 12 |
Fraction Csp3 | 0.39 |
Num. rotatable bonds | 11 |
Num. H-bond acceptors | 9.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 126.76 |
TPSA ? Topological Polar Surface Area: Calculated from |
135.14 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.84 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.86 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
4.09 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.68 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.42 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.58 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.61 |
Solubility | 0.122 mg/ml ; 0.000247 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-4.32 |
Solubility | 0.0237 mg/ml ; 0.0000479 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-5.54 |
Solubility | 0.00144 mg/ml ; 0.00000292 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
Low |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
Yes |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
Yes |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
Yes |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
Yes |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-7.99 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
1.0 |
Egan? Egan (Pharmacia) filter: implemented from |
1.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<2.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
4.4 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.2% | To a solution of 13g of the compound of Formula V in 350 ml of anhydrous tetrahydrofuran and 90ml of methanol, was added a solution of 13 ml of 1M diethylmethoxyborane in tetrahydrufuran at-78 C, and the mixture was stirred at the same temperature for 30 minutes. To the mixture, was added 1.3g of a sodium borohydride and the mixture was stirred for another 3 hours. Acetic acid (16ml) was added thereto, and the mixture was adjusted to pH 8 with saturated sodium bicarbonate and extracted with ether. The organic layer was washed with water, dried and evaporated ether under reduced pressure. To the resulting residue, methanol was added and the mixture was evaporated under reduced pressure. The resulting residue was subjected to column chromatography of silica gel eluting with methylene chloride/ether (3: 1) to give 11. 4g of dihydroxy compound, methyl 7- [4-fluorophenyl)-6-isopropyl-2- (N-methyl-N- methylsulphonylamino) pyrimidin-5-yl]- (3R, 5S)-dihydroxy- (E)-6-heptenate (VI) as syrup. Yield: 85. 2percent | |
85.2% | (5); To a solution of 13 g of compound iii in 350 mL of anhydrous THF and 90 mL of methanol, a solution of 29.7 mL of 1 M diethylmethoxyborane-THF is added at -78°C. The mixture is stirred at the same temperature for 30 minutes. NaBIL; (1.3 g) is added and the mixture is stirred for 3 hours. Acetic acid (16 mL) is added thereto, and the mixture is adjusted to pH 8 with saturated sodium bicarbonate and extracted with ether. The organic layer is washed with water, dried, and the ether is evaporated under reduced pressure. Methanol is added to the resulting residue and the mixture is evaporated three times under reduced pressure. The resulting residue is subjected to column chromatography on silica gel, eluting with methylene chloride/ether (3/1) to give 11.4 g (Yield: 85.2percent) of methyl 7-[4-(4-fluorophenyl)-6-iso-propyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenate (compound iv) as a syrup. | |
Example-4Preparation of methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl amino)-pyrimidin-5-yl1-(3R,5S)-dihvdroxy -(E)-6-heptenate (Compound-Q Coinpound-CTetrahydrofuran (1800 ml) was taken in a flask and cooled to -90 °C. To this sodiumborohydride (10 g) and diethyl methoxyborane (1.0 M solution in THF) was added and maintained for 30 minutes. To this reaction mixture, solution of methyl 7-[4- (4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R) -3-hydroxy-5-oxo-(E)-6-heptenate (Compound A) (100.0 g Compound A dissolved in 700 ml THF and 700 ml methanol) was slowly added and maintained at a temperature - 90 0C for 2-3 hours. Acetic acid was added to the reaction mass and the temperature was raised to room temperature. To this reaction mass, a mixture of ethyl acetate and water was added. Organic layer was washed with brine solution and dried over sodium sulfate. Methanol was added to the residue and evaporated to yield methyl 7-[4-(4-flourophenyl)- 6-isopropyl:2-(N-methyl-N-methylsuIfonylamino)-pyrimidin-5-yl]-(3R,5S)-dihydroxy- (E)--heptenate |
With methanol; sodium tetrahydroborate; diethyl methoxy borane; In tetrahydrofuran; at -90 - -80℃;Inert atmosphere;Product distribution / selectivity; | In a round bottom flask 2000 ml Tetrahydrofuran (THF) was added under the nitrogen atmosphere and cooled to -90°C then 1Og sodium borohydride was added followed by 230ml diethylmethoxyborane (1 M solution in THF) in 90-120mins. In this reaction mass, mixture of lOOg of Methyl -7-[4-(4-fiourophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylaniino)-pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6-heptenate5 700 ml THF and 700 ml methanol was added for a duration of 90-120min then stirred for 2 hrs at -90 to -80°C. After the completion of reaction, 124 ml acetic acid was added and stirred for 30-60 min at same temperature. Above reaction mass was diluted with 1500ml ethyl acetate and washed with brine solution. To the organic layer, 500 ml DM water was added and pH was adjusted to neutral by ~ 500 ml 6 percent sodium bicarbonate solution. Both the layers were separated Sc the organic layer was dried over sodium sulphate. The organic layer was concentrated at 40-450C. Above concentrated mass was diluted with 900ml ethyl alcohol and then cooled to 0°C. Sodium hydroxide solution was added in 60- 90 min. The reaction mass was stirred for 30 min at room temperature and the pH was adjusted to 11.5-12.0 by using ~ 4 percent sodium hydroxide solution. In this reaction mass, 1Og activated carbon was added and stirred for 20 min. The reaction mass was filtered and washed with ethanol/DM water mixture. The reaction mass was concentrated up to thick residue at 40-45°C. To this concentrated mass, 500 ml DM water was added followed by 1000ml ethyl acetate and the pH was adjusted to 3.5- 4.0 with 1:4 aqueous hydrochloric acid. Both the layers were separated and the organic layer was washed with brine solution.The organic layer was dried over sodium sulphate and concentrated till dryness at 40-45°C. To the above concentrated mass, 1000 ml acetonitrile was added stirred at room temperature for half an hour. Slowly 20.5 g (S)-2-amino-3, 3 -dimethyl butane was added and stirred for almost 2 hrs. The solid was filtered and washed with acetonitrile and diisopropyl ether. Finally the solid was dried for 6-9 hrs at 40-45°C.Above obtained (S)-2-amino-3, 3 -dimethyl butane salt of rosuvastatin was suspended in 1000 ml isopropanol followed by 100 ml methanol. This reaction mass was heated for half an hour at 60-80°C then stirred for 3-4 hrs at 5-1O0C. The solid was filtered washed with isopropanol and diisopropyl ether. 95 gms of (S)-2-amino-3, 3 -dimethyl butane salt of rosuvastatin was obtained. | |
The synthetic route is shown in flow diagram 3:The detailed preparing process is as follows:300mL anhydrous THF, 85mL anhydrous methanol and 6.3g (3R,6E)-7-[4-(4-flurophenyl)-6-(1-methylethyl)-2-[methyl (methyl sulfonyl) amino]-5-pyrimidyl]-3-hydroxy-5-oxo-6-methyl heptenoate were added to a 500mL reaction flask.Subsequently, the reaction system was flushed with N2, and the mixture was stirred until the solid was dissolved.The reaction mixture was cooled to -85°C by using liquid nitrogen, and 12.8mL THF solution containing 1M diethyl methoxyl borane was added at constant speed at -85°C within 30 minutes.The mixture was stirred for 60 minutes at -85°C, subsequently, 0.7g sodium borohydride was uniformly added in several portions.The addition process took about 90 minutes, and then the mixture was allowed to stand at -85°C for 6 hours.The temperature of the mixture was increased to 30°C within 2 hours and the reaction lasted for 3 hours at 30°C.Subsequently, 1.2g glacial acetic acid was added, and the obtained solution was vacuum distilled to remove mixed solvent containing methanol-THF at 50°C. As a result, oily product was obtained.50mL methanol was added to dissolve the oily product.The obtained solution was vacuum distilled to remove methanol at 50°C.Then 50mL methanol was added to dissolve the oily product, the obtained solution was vacuum distilled to remove methanol at 50°C, and the obtained oily product remained in the reaction flask.Afterwards, 50mL ethyl acetate and 50mL water were added to the reaction flask and stirred for 15 minutes, subsequently, the mixture was allowed to stand for layering.The obtained water phase was extracted twice with ethyl acetate (30mL each time), where the water phase was stirred for 15 minutes during each extraction, and the obtained mixture was allowed to stand for layering.Then the organic phases were combined and washed with saturated sodium bicarbonate solution (40mL).Subsequently, the obtained mixture was washed twice with saturated sodium chloride solution (40mL each time), where the solution was stirred for 15 minutes during each washing.It was then allowed to stand for layering.The water phase was removed, while 2g anhydrous sodium sulfate was added to the organic phase and stirred for 30 minutes.Then anhydrous sodium sulfate was removed by pumping filtration.The filtrate was vacuum distilled to remove ethyl acetate at 50°C.As a result, 6.0g oily (3R,5S,6E)-7-[4-(4-flurophenyl)-6-(1-methyl ethyl)-2-[methyl (methyl sulfonyl) amino]-5-pyrimidyl]-3,5-dihydroxy-6-methyl heptenoate was obtained, and could directly be used in the next step.; Example 8. Preparation of crystalline (3R, 5S, 6E)-7-[4-(4-flurophenyl)-6-(1-methyl ethyl)-2-[methyl (methyl sulfonyl) amino]-5-pyrimidyl]-3, 5-dihydroxy-6-heptenoic-3-methyl butyrate (crystal form I)After 80mL ethyl ether and 1.5mL acetonitrile was added to 10g (3R,5S,6E)-7-[4-(4-flurophenyl)-6-(1-methyl ethyl)-2-[methyl (methyl sulfonyl) amino]-5-pyrimidyl]-3,5-dihydroxy-6-heptenoic-3-methyl butyrate. The mixture was heated until the mixture was fully dissolved, then it was cooled to 0-5°C and devitrified for 24 hours. As a result, 7.7g crystalline solid was obtained with a yield of 77percent. The XRD spectrum is shown in Figure 5. | ||
With methanol; sodium tetrahydroborate; diethyl methoxy borane; In tetrahydrofuran; at -90 - -80℃; for 6h;Inert atmosphere; | Example 3Preparation of methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-iV- methylsulfonylamino)pyrimidin-5-yl]-(3R,5S)-dihydroxy-(.pound.)-6-heptenate (VI)A mixture of tetrahydrofuran (800 ml) and methanol (200 ml) was cooled to -90 ° to - 75°C under nitrogen atmosphere. Sodium borohydride (7.7g) was added and the reaction mass was stirred for 30 minutes at the same temperature under nitrogen atmosphere. Diethylmethoxyborane (100 ml) was added to the resulting reaction mixture and was stirred for few minutes at same temperature. Methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2- (N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(3 ?)-3-hydroxy-5-oxo-(E)-6- heptenate (lOOg) taken in a mixture of tetrahydrofuran (800 ml) and methanol (200 ml), was added to the reaction mixture over a period of 4.0 hour at -90° to -80°C under nitrogen atmosphere. The reaction mass was stirred for 2.0 hours at -90° to -80°C. After the reaction completion, the temperature of reaction mass was raised to 0°C and then to room temperature. The pH of the resulting mixture was adjusted to 9.0-9.5 using 5percent aqueous acetic acid solution. To the resulting mixture, water (200 ml) and methyl tertiary butyl ether (500 ml) were added and was stirred for few minutes. The organic layer was separated, and concentrated under vacuum at 45-50°C to obtain the title compound as thick oily mass. | |
With sodium tetrahydroborate; diethyl methoxy borane; In tetrahydrofuran; methanol; at -105 - 95℃;Product distribution / selectivity; | Sodium borohydride (3.2g) was added to a cold solution of tetrahydrofuran (130 ml) and methanol (30 ml) at -105°C to -95°C, followed by addition of diethylmethoxyborane (28ml, 1M in THF). Thereafter, a solution of 7-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl- methyl-amino)-pyrimidin-5-yl]-3-hydroxy-5-oxo-hept-6-enoic acid methyl ester (20 g) in tetrahydrofuran (30 ml) and methanol (10 ml) was added to above reaction mass at -105°C to -95°C. After completion of reaction, acetic acid (15.4 ml) was added to the reaction mass and temperature of reaction mass was raised to 20-25 °C. Solvents were distilled off completely under vacuum from the reaction mixture. Methanol (40 ml) was added to resulting residue and distilled out. Water (100 ml) was added to resulting residue followed by extraction of product with ethyl acetate (100 ml). Organic layer was washed with saturated solution of sodium bicarbonate and then with saturated sodium chloride solution. Resulting organic layer was concentrated under vacuum to give 22 g of title compound having purity 94.93 percent; and anti-isomer- 0.96 percent by HPLC. | |
10.7 g | With sodium tetrahydroborate; diethyl methoxy borane; In tetrahydrofuran; methanol; at -78 - -75℃; for 1.5h; | at -78°C internal reactor temperature, tetrahydrofuran (THF) and 80 mL in a mixed solution of 20 mL of methanol was added NaBH4 (sodium borohydride) 1 g (1.3 eq) was added thereto. After 15 minutes, 50percent Et2BOMe in THF solution (diethyl-methoxy-borane, DEMB) was added dropwise 2.53 mL (0.5 eq). Dissolving the compound of formula g 10 (0.02 mol, 99.1percent purity) in 20 mL THF, was slowly added dropwise thereto for about one hour while maintaining the reactor internal temperature of -78 ~ -75°C. After the dropwise addition the internal temperature was stirred for 30 minutes at -78 ~ -75°C. After the slow dropwise addition of 10 mL 35percent aqueous hydrogen peroxide solution to the reaction solution was heated to an internal temperature of 0 .150 mL of ethyl acetate and 100 mL of purified water was added to the reaction solution and extraction. To remove the water layer and 10percent NaHCO3aqueous solution 100 mL, 10percent Na2SO3was washed with 100 mL aqueous solution and the organic layer was washed in turn with 10percent NaCl solution 100 mL. and concentrated in vacuo at 45 ~ 50°C the organic layer to give the compound formula III (R= Me ) and 10.7 g was obtained yellow oil with an HPLC purity of 98.5percent. |
6 g | rous methanol 85 ml, 6.3 g TP-13 was added and the reaction was purged with nitrogen and stirred until all the TP-13 was dissolved.Cooled to -80 ° C to -85 ° C with liquid nitrogen and 12.8 ml of a tetrahydrofuran solution of 1 M diethylmethoxyborane was added dropwise to control the rate of dropping to keep the temperature from -80 ° C to -85 ° C And the dropping time is about 30 min.Maintain the temperature between -80 ~ -85 , continue stirring 55 ~ 60min.And then evenly add 0.7 g sodium borohydride, about 80 ~ 90min after adding, to maintain the temperature between -80 ~ -85 , this process requires 5.5 ~ 6h, the end of the reaction.And then heated to 20 ° C to 30 ° C in 2 hours. After 2 to 3 hours of continuous incubation, 1.2 g of glacial acetic acid was added, followed by distillation under reduced pressure at 45 ° C to 55 ° C to remove the organic solvent mixed with methanol and tetrahydrofuran to give an oil Things.After adding 50 ml of methanol to dissolve the oil, it was distilled under reduced pressure at 45 ° C to 55 ° C to remove methanol to obtain an oil.The mixture was further added with 50 ml of methanol to dissolve the oil and distilled under reduced pressure at 45 ° C to 55 ° C to remove methanol to give the final oil.Then, 50 ml of ethyl acetate and 50 ml of water were added to the final oil, and the mixture was stirred for 10 to 15 minutes. The mixture was allowed to stand and the aqueous layer was repeatedly extracted twice with ethyl acetate. Each time, 30 ml of acetic acid Ethyl ester, each time for 10 to 15 minutes, static liquid separation, and finally the organic layer.The resulting organic layer was washed successively with 40 ml of a saturated aqueous solution of sodium bicarbonate and twice with a saturated aqueous solution of sodium chloride, each time with an amount of 40 ml of a desaturated sodium chloride aqueous solution, and the mixture was stirred for 10 to 15 minutes Set the liquid, discard the water layer.The organic layer was added with 2 g of anhydrous sodium sulfate, stirred for 30 min, and the anhydrous sodium sulfate was removed by suction filtration. The filtrate was distilled at a temperature of 40 ° C to 50 ° C under reduced pressure to remove the ethyl acetate organic solvent to obtain 6.0 g of RSM oil | |
15.8 g | With methanol; sodium tetrahydroborate; diethyl methoxy borane; In tetrahydrofuran; at -80 - 25℃; for 8.5h;Inert atmosphere; | S3: Under nitrogen protection, 110 g of tetrahydrofuran and 27.5 g of methanol were added to the reaction flask, the temperature was lowered to -80 ± 5 ° C, 3.19 g of sodium borohydride was added, and the mixture was stirred for 15 minutes, and the temperature was controlled to -80 ± 5 ° C, and 49.5 g was added dropwise. The solution of percentEt2BOMe in tetrahydrofuran was diluted for 1 h. After the end of the incubation, 15.84 g of the S2 product in tetrahydrofuran solution was added dropwise, and the dropping temperature was controlled to -80 ± 5 ° C. After 4 h, the temperature was raised to 4.5 h and the temperature was raised to 20-25 ° C, then adjusted with glacial acetic acid PH = 6.0-7.0, stirred for 30 minutes, re-test PH = 6.0-7.0 qualified, concentrated to dryness under reduced pressure, the end of concentration, then add ethyl acetate and water to stir and dissolve The mixture was allowed to stand for stratification, and the water layer was discarded. The organic layer was washed once with saturated brine, and the organic layer was collected. The organic layer was concentrated at 45 ° C to give an oil (3R, 5S)-7-[4-(4-fluorobenzene) Methyl-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-3,5-dihydroxy-6(E)-heptenoic acid methyl ester 15.8 g ; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 10: Preparation of Methyl 7-[4-(4-flouropheny.)-6-isopropyl-2-(N-methyl- N-methylsulfonylamino)-pyrimidin-5-yl] - (3R)-3hydroxy-5-oxo-(E)-6-heptenate (Rosuvastatin intermediate)A solution of 25 g 4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl amino)-5-pyrimidine carbaldehyde, 55 g Methyl (3R)-3-(t-butyldimethylsilyloxy)-5-oxo- 6-triphenyl phosphoranylidene hexanoate and acetonitrile was refluxed for about 20 hrs. The reaction mass was concentrated under vacuum. To this cyclohexane was added. The reaction mass was stirred and filtered. Filtrate was Concentrated under u/v and taken into acetonitrile, cooled to 0 C. To this solution of hydrogen fluoride (100 ml) was added drop wise in acetonitrile under ice cooling, and the mixture was warmed to room temperature and stirred for 1-3 hrs. To this a mixture of DM water and dichloromethane was added and neutralized with sodium bicarbonate solution. The reaction mixture was stirred and layers were separated. The organic layer was washed with water and brine solution. To the concentrated IPA was added, stirred, and filtered. The obtained solid was washed IPE and dried to give Methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)-pyrimidin-5-yl] - (3R)-3-hydroxy-5-oxo-(E)-6-heptenate(32 g). |
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