CN101376647B - Method for synthesizing rosuvastatin intermediate and rosuvastatin - Google Patents
Method for synthesizing rosuvastatin intermediate and rosuvastatin Download PDFInfo
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- CN101376647B CN101376647B CN2008101467326A CN200810146732A CN101376647B CN 101376647 B CN101376647 B CN 101376647B CN 2008101467326 A CN2008101467326 A CN 2008101467326A CN 200810146732 A CN200810146732 A CN 200810146732A CN 101376647 B CN101376647 B CN 101376647B
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Abstract
The invention provides a synthetic method of rosuvastatin calcium, which is characterized in that a compound 6 and branched chain react under the action of 2,2,6,6,-tetramethylpiperidine and n-butyl lithium to generate a compound 7, the reaction temperature is increased to minus 30 DEG C and the aspects such as reaction solvent and reaction reagent are improved so that the total reaction route has the advantages of mild condition, low device requirement and suitability for industrial production. Meanwhile, another improved synthetic route of rosuvastatin calcium comprises the following steps: converting esters into acids, synthesizing esters again, and synthesizing the rosuvastatin calcium. The rosuvastatin calcium purity is as high as 99.8%.
Description
The art field
The present invention relates to intermediates preparation in the synthetic method of a kind of Rosuvastatin, Rosuvastatin calcium salt and the building-up process.
Background technology
Rosuvastain calcium is that Japanese Shionogi Seiyaku Kabushiki Kaisha develops, screens an aminopyridine derivative that obtains at the end of the eighties in last century.Afterwards, 3-hydroxy-3-methylglutaryl-coenzyme A of new generation (HMG-CoA) reductase inhibitor that AstraZeneca company develops in the world wide except that East Asian countries such as Japan, go on the market in Canada first in February, 2003, general Rosuvastatin calcium by name, according to the INN partials, with its called after rosuvastain calcium.Chemistry is by name: two [(E)-and 7-[4-(4-fluorophenyl)-6-sec.-propyl-2-[methyl (methylsulfonyl) amino] pyrimidine-5-yl] (3R, 5S)-3,5-dihydroxyl-6-heptenoic acid] calcium salt, molecular formula is (C
22H
27FN
3O
6S)
2Ca.Structural formula is:
Patent US5260440 and patent WO03/097614 disclose the synthetic route of aminopyridine derivative, rosuvastain calcium respectively, and wherein the synthetic route of the disclosed rosuvastain calcium of patent WO03/097614 comprises the steps:
The synthetic route of the rosuvastain calcium of above-mentioned two patent disclosures is long, the part reagent that uses is relatively more expensive, the toxicity of organic solvent is bigger, and in the carbonyl chiral reduction process of side chain, the purity of active enantiomer is low, and productive rate is on the low side, so, above synthetic method is time-consuming, uneconomical, improper suitability for industrialized production.
Patent WO00/49014 discloses another synthesizing rosuvastatin spit of fland calcium intermediate 6-[2-(4-is to fluorophenyl) 6-sec.-propyl-2-(N-methyl-N-first sulfo group) amino)] pyrimidine-5-base (4R, 6S)-2, the synthetic method of 2-dimethyl [1,3] diepoxy-4-acetate trimethyl carbinol ester and rosuvastain calcium thereof.Main building-up process is divided into following three steps: (1) [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl alcohol synthesizes N-[5-brooethyl-4-(4-fluorophenyl)-6-sec.-propyl-2-pyrimidyl with the phosphorus tribromide bromination]-N-methyl Toluidrin; (2) go up step product adding phenylbenzene methoxy base phosphine heating reflux reaction and obtain solid product; (3) above-mentioned solid product is cooled to-75 ℃ under nitrogen protection in tetrahydrofuran solvent, adds two silica-based amine sodium of front three then, adds the toluene solvant reaction of side chain again, obtains solid matter through aftertreatment.
This synthetic route is for said synthesis route, and its synthetic route is shorter, in this synthetic route, two chiral carbon that are connected to hydroxyl of side chain do not need chiral reagent to produce, so this synthetic route is simple, reagent cost is lower, be fit to suitability for industrialized production.But in this patent building-up process, temperature of reaction is extremely low, reaction process operation is very complicated, though improved with respect to the productive rate of other synthetic routes, awaits further to improve the purity of the productive rate and the final product of rosuvastain calcium, reduces cost.
Summary of the invention
The synthetic method that the purpose of this invention is to provide relevant intermediate in a kind of synthesizing rosuvastatin spit of fland calcium and the preparation process, the reaction conditions of this method are relatively gentleer, and employed reagent is less expensive, the purity height of the rosuvastain calcium that obtains, productive rate height.
For realizing purpose of the present invention, the technical scheme of employing is:
Described side chain is:
Wherein, R
1Be the cycloalkyl of the alkyl or 3-6 the carbon atom of 1-10 carbon atom, the straight chained alkyl of its preferred 1-5 carbon atom; Z is-PPh
3 +Br
-Or-PO (OAk)
2Or-POAr
2, its Ak is the alkane of 1-4 carbon atom, Ar is the aromatic hydrocarbons of 6-8 carbon atom,
It is characterized in that, make compound 62,2,6, the following and branched chain reaction of the effect of 6-tetramethyl piperidine, n-Butyl Lithium generates compound 7.
The organic solvent that reaction is used selects excellent tetrahydrofuran (THF) organic solvent as tetrahydrofuran (THF), hexane, chloroform, toluene etc.
Described compound 6 is-25 ℃～-50 ℃ with the temperature that the reaction of side chain is carried out, and preferred temperature is-28 ℃～-40 ℃, and more preferably temperature is-28 ℃～-35 ℃.
Described compound 6 and adding 2,2,6, the amount of substance ratio of 6-tetramethyl piperidine is 1: 4.5～5.5, the amount ratio of its preferred substance is 1: 4.5～5.0.
Described compound 6 is 1: 1.0～2.0 with the ratio of the amount of substance of side chain, and the amount ratio of its preferred substance is 1: 1.0～1.5.
The reaction of The compounds of this invention 6 and side chain is 2,2,6, carries out Wittig reaction or Wittig-Horner reaction in this alkaline environment of 6-tetramethyl piperidine, and this is that the phosphonic acid ester carbanion can react with aldehyde ketone under the effect of alkali.In the prior art, the normal alkali that adds is n-Butyl Lithium, and patent WO00/49014 adds two (front three is silica-based) amine sodium in this step reaction, the reaction optimum temps is at-74 ℃, the aftertreatment of resultant is very complicated, needs to obtain final product through repetitious distillation, washing.The inventor is in synthetic this step reaction, the unexpected discovery, when the environment of compound 6 and branched chain reaction changes, promptly except adding alkaline reagents n-Butyl Lithium commonly used, in organic solvent, add 2 again, 2,6, behind the 6-tetramethyl piperidine, this is reflected under-28 ℃～-35 ℃ higher relatively temperature, can generate compound 7, because the phosphonic acid ester carbanion is 2,2,6, can be in this environment that the 6-tetramethyl piperidine provides at-28 ℃～-35 ℃ stable existences, though from the yield analysis of reaction product, the present invention is lower than prior art slightly, from the angle of suitability for industrialized production, experimental program provided by the invention can make this step be reflected at-28 ℃～-35 ℃ to carry out, and tackles the equipment requirements that industrial production is used so mutually, operating procedure and keep the required energy of ultralow temperature all to be significantly improved for a long time.
Compound 6 of the present invention is to generate bromide compounds 5 by compound 4 and phosphorus tribromide, afterwards compound 5 again with two aromatic hydrocarbons alkoxyl group phosphines or phosphonic acid ester or triphenylphosphine reacting generating compound 6.
Wherein, Z is-PPh
3 +Br
-Or-PO (OAk)
2Or-POAr
2, its Ak is the alkane of 1-4 carbon atom, Ar is the aromatic hydrocarbons of 6-8 carbon atom.
Above-mentioned compound 4 is 5 ℃～15 ℃ with the temperature that the reaction of phosphorus tribromide is carried out.
The solution of above-mentioned phosphorus tribromide was added drop-wise in the dichloromethane solvent of compound 4 in 0.75～1.25 hour.
After above-claimed cpd 4 reacts with phosphorus tribromide, separatory after the frozen water washing, the organic layer behind the separatory uses the saturated common salt water washing.
The synthetic method of compound 4 of the present invention is:
A) p-Fluorobenzenecarboxaldehyde, isobutyryl methyl acetate and urea reacting generating compound 1 under cuprous chloride, vitriolic effect;
B) compound 1 reacting generating compound 2 under the effect of nitric acid;
C) compound 2 is under the potassium alkaline condition, successively with toluene sulfonyl chloride, methylsulfonyl methylamine reacting generating compound 3;
D) compound 3 is reduced to compound 4 through diisobutyl aluminium hydride.
The compound 7 that the present invention makes successively makes compound 8 rosuvastain calciums with 30% methylamine-ethanol, sodium hydroxide, calcium chloride reaction after hydrochloric acid hydrolysis.
The invention provides another kind of rosuvastain calcium synthetic route, as shown below, comprised following steps:
1) compd A hydrolysis in basic solution is adjusted to solution with acid then and is acid, obtains compd B;
2) compd B and XR ' reacting generating compound C;
3) Compound C priority and sodium hydroxide, water-soluble Ca salt reacting generating compound D;
Wherein, R
2Alkane for 1-4 carbon; R ' among the XR ' is the cycloalkyl of the alkyl or 3-6 the carbon atom of 1-10 carbon atom, the straight chained alkyl of its preferred 3-5 carbon atom; X is Br or I, its preferred Br.
The synthetic method referenced patent US5260440 of said synthesis route starting material compound A.
Basic solution in the described step 1) is CsOH, KOH, NaOH, Ba (OH)
2Or Ca (OH)
2The aqueous solution, preferred sodium hydroxide solution, wherein the concentration of sodium hydroxide solution is 0.1～5.0mol/L, preferred 1.0～2.0mol/L.
The temperature of reaction of compd A and sodium hydroxide solution is 20～80 ℃ in the described step 1), preferred 40～55 ℃
The reaction times of compd A and sodium hydroxide is 3～12 hours in the described step 1), preferred 4～6 hours.
PH:2～4 of the acidic solution in the described step 1) after acid is regulated.
Described step 2) compd B and XR ' react at alkaline condition in.
Described alkali is salt of wormwood, sodium bicarbonate, saleratus, yellow soda ash, sodium-acetate, ammoniacal liquor, Trimethylamine 99, triethylamine, Tributylamine, pyridine, morpholine or piperidines, its preferred salt of wormwood or triethylamine.
Described step 2) the amount of substance ratio of compd B and XR ' is 1: 1～10 in, it is preferably 1: 4～and 6.
Described step 2) reaction times of compd B and XR ' is 12～36 hours in, and they preferred 15～20 hours.
Calcium salt in the described step 3) is calcium chloride, calcium acetate, nitrocalcite or calcium hydroxide, its preferred calcium acetate.
The temperature that chemical reaction carries out in the described step 3) is 5 ℃～20 ℃.
In patent US5260440, similar in the ester of compd A directly through alkaline hydrolysis, obtain rosuvastain calcium with the water-soluble calcium reactant salt afterwards, because the purity of the compounds of the ester that directly obtains is bad, so cause the purity of finished product rosuvastain calcium on the low side.
The present invention is for becoming water-fast acid with acidifying after the compd A alkaline hydrolysis, make acid well separate with impurity, the purified acid that obtains becomes ester once more with halohydrocarbons reaction again, so again, the purity height of the ester compound C that obtains, prior art is that compd A is carried out purifying by physical method, the operation more complicated, and the cost of input is also high, but purification effect is not good, influences the purity of final product.The purity height of the rosuvastain calcium that the Compound C process series reaction that the present invention obtains obtains reaches 99.5%.
Two synthetic routes provided by the invention, article one synthetic route by the change to factors such as reaction reagent, reaction solvents make reaction conditions temperature, the technical process of entire reaction route easy, lower to the requirement of equipment, the purity of products therefrom helps suitability for industrialized production; In the second synthetic route in view of prior art in the unfavorable defective of purity of Rosuvastatin calcium, the present invention is by changing ester compound A once more into the process that acid becomes ester then, make the purity height of the new ester compound C of gained, thereby the target product rosuvastain calcium that obtains is pure also very high, and yield does not compared with prior art have obvious variation.
Embodiment
Embodiment 1
The synthetic method of compound 1:
Add in the 10L reactor that 2.5L methyl alcohol, 0.8kg (6.45mol) p-Fluorobenzenecarboxaldehyde, 0.85kg (5.90mol) isobutyryl methyl acetate, 1kg (16.67mol) urea, cuprous chloride are an amount of, the sulfuric acid of 2.3L1mol/L, be heated to backflow (65～68 ℃ of interior temperature) 10h, ice-water bath is cooled to 0 ℃, suction filtration behind the continuation stirring 4h, the methyl alcohol drip washing of gained solid, after 60 ℃ of oven dry, get off-white color crystal 1.594kg, yield 92.6% with loft drier.The purity of measuring compound 1 through high performance liquid phase is 95%.
Embodiment 2
The synthetic method of compound 1:
The sulfuric acid that in the 10L reactor, adds 2.5L methyl alcohol, 0.8kg (6.45mol) p-Fluorobenzenecarboxaldehyde, 0.85kg (5.90mol) isobutyryl methyl acetate, urea 0.885kg (14.74mol), 2.6L1mol/L, be heated to backflow (65～68 ℃ of interior temperature) 20h, ice-water bath is cooled to 10 ℃, suction filtration behind the continuation stirring 5h, the methyl alcohol drip washing of gained solid, after 60 ℃ of oven dry, get off-white color crystal 1.574kg, yield 91.4% with loft drier.The purity of measuring compound 1 through high performance liquid phase is 95.2%.
Embodiment 3
The synthetic method of compound 2:
The nitric acid, the Sodium Nitrite that add 5L65～68% in the 10L reactor are an amount of, temperature control adds 1.5kg (5.14mol) compound 1 in the time of 20 ℃, continue at 20～25 ℃ of reaction 1h, and the TLC detection reaction is complete, in reaction solution, add 3L water, drip 30% sodium hydroxide solution 20 ℃ of temperature controls the pH of reaction solution transferred to 8,, be cooled to 5 ℃, suction filtration behind the continuation stirring 1h, the gained solid washes with water, obtains light yellow solid 1.411kg, yield 94.7% with loft drier after 80 ℃ of oven dry.The purity of measuring compound 2 through high performance liquid phase is 92.8%.
Embodiment 4
The synthetic method of compound 3:
Add n-butyl acetate 10L in the 20L reactor; 1.65kg (5.69mol) compound 2; Anhydrous potassium carbonate 0.5kg; under nitrogen protection; add Tosyl chloride 0.8kg (4.21mol); temperature is 50 ℃ in being heated to, reaction 1h, and the TLC detection reaction is complete; add methylsulfonyl methylamine 0.682kg (6.259mol) again; backflow (about 124 ℃ of interior temperature) 3h, TLC detect and still have minute quantity raw material unreacted intact, are cooled to room temperature; pour in the water that volume is 11L; stir 5min, leave standstill 20min, separatory; water layer extracts with n-butyl acetate; merge organic layer, and wash with water, concentrating under reduced pressure obtains the off-white color solid; use the Virahol recrystallization; loft drier dry white solid 1.843kg, yield 85.0%, the purity of measuring compound 3 through high performance liquid phase is 92.8%.
Embodiment 5
The synthetic method of compound 4:
In the 20L reactor, add toluene 10L and 1.3kg (3.412mol) compound 3; 40 ℃ of stirrings of temperature make its whole dissolvings in being heated to; be cooled to-5 ℃ in nitrogen protection; drip the toluene solution of 25% diisobutyl aluminium hydride (DIBAL-H); 0～5 ℃ of temperature control drips off in 1～2h, continues reaction 1h; the TLC detection reaction is complete; reaction solution is slowly poured in the hydrochloric acid soln, added ethyl acetate extraction again, stir 15min; leave standstill 20min; separatory, organic layer are used 5% sodium hydrogen carbonate solution successively; water; the saturated common salt water washing concentrates; filter; obtain white solid 1.024kg 70 ℃ of dryings, yield 85.0%.The purity of measuring compound 4 through high performance liquid phase is 98%.
Embodiment 6
The synthetic method of compound 5:
Add 10L methylene dichloride and 0.93kg (2.634mol) compound 4 respectively in the 20L reactor, at 10 ℃ of dichloromethane solutions that drip 0.5kg (1.845mol) phosphorus tribromide, drip off in the 1h, continue reaction, the TLC detection reaction is complete.Reaction solution is poured in the frozen water, stirred 5min, leave standstill 10min, the saturated common salt water washing of separatory, organic layer, anhydrous sodium sulfate drying filters, and gets white solid 0.965kg, yield 88.04% after filtrate concentrates.The purity of measuring compound 5 through high performance liquid phase is 92%.
Embodiment 7
The synthetic method of compound 5:
Add 10L methylene dichloride and 0.93kg (2.634mol) compound 4 respectively in the 20L reactor, at 15 ℃ of dichloromethane solutions that drip 0.5kg (1.845mol) phosphorus tribromide, drip off in the 1.20h, continue reaction, the TLC detection reaction is complete.Reaction solution is poured in the frozen water, stirred 5min, leave standstill 10min, the saturated common salt water washing of separatory, organic layer, anhydrous sodium sulfate drying filters, and gets white solid 0.947kg, yield 86.4% after filtrate concentrates.The purity of measuring compound 5 through high performance liquid phase is 91.8%.
Embodiment 8
The synthetic method of compound 6:
In the 10L reactor, add toluene 6L and 0.9kg (2.163mol) compound 5, be heated to whole dissolvings, add 0.4kg (1.852mol) phenylbenzene methoxy base phosphine again, be cooled to 15 ℃ of reaction 2h, TLC detects has a small amount of raw material unreacted intact, and ice-water bath is cooled to 5 ℃, filter, solid toluene drip washing, drying obtains white solid 1kg, yield 90.5%.High performance liquid phase: 99.5%.
Embodiment 9
The synthetic method of compound 6:
In the 10L reactor, add toluene 6L and 0.9kg (2.163mol) compound 5, be heated to whole dissolvings, add 0.6kg (2.778mol) phenylbenzene methoxy base phosphine again, be cooled to 10 ℃ of reaction 2.5h, TLC detects has a small amount of raw material unreacted intact, ice-water bath is cooled to 5 ℃, filter, solid toluene drip washing, drying obtains white solid 1.051kg, yield 90.5%, the purity of measuring compound 6 through high performance liquid phase is 99.5%.
Embodiment 10
The synthetic method of compound 6:
In the 10L reactor, add toluene 6L and 0.9kg (2.163mol) compound 5, be heated to whole dissolvings, add 1.2kg (5.556mol) phenylbenzene methoxy base phosphine again, be cooled to 20 ℃ of reaction 1.5h, TLC detects has a small amount of raw material unreacted intact, ice-water bath is cooled to 5 ℃, filter, solid toluene drip washing, drying obtains white solid 1.062kg, yield 91.4%, the purity of measuring compound 6 through high performance liquid phase is 97.3%.
Embodiment 11
The synthetic method of compound 7:
In the 20L reactor, add 2.5L tetrahydrofuran (THF), 2kg (14.18mol) 2; 2; 6; 6-tetramethyl piperidine; under nitrogen protection, be cooled to-30 ℃; add n-Butyl Lithium-hexane solution, add 1.6kg (2.980mol) compound 6 and 1kg (3.676mol) side chain, insulation reaction 2h in batches; at room temperature add glacial acetic acid solution 5L; tetrahydrofuran (THF) is removed in underpressure distillation, adds toluene and stirs layering, collected organic layer; the organic layer washing; drying, underpressure distillation get 0.86kg oily compound 7, yield 50%.
Embodiment 12
The synthetic method of compound 7:
In the 20L reactor, add 2.5L tetrahydrofuran (THF), 2.10kg (14.91mol) 2; 2; 6; 6-tetramethyl piperidine; under nitrogen protection, be cooled to-25 ℃; add n-Butyl Lithium-hexane solution, add 1.6kg (2.980mol) compound 6 and 1.21kg (4.47mol) side chain, insulation reaction 2h in batches; at room temperature add glacial acetic acid solution 5L; tetrahydrofuran (THF) is removed in underpressure distillation, adds toluene and stirs layering, collected organic layer; the organic layer washing; drying, underpressure distillation get 0.906kg oily compound 7, yield 52.7%.
Embodiment 13
The synthetic method of compound 7:
In the 20L reactor, add 2.5L tetrahydrofuran (THF), 2kg (14.18mol) 2; 2; 6; 6-tetramethyl piperidine; under nitrogen protection, be cooled to-40 ℃; add n-Butyl Lithium-hexane solution, add 1.6kg (2.980mol) compound 6 and 0.811kg (2.980mol) side chain, insulation reaction 2h in batches; at room temperature add glacial acetic acid solution 5L; tetrahydrofuran (THF) is removed in underpressure distillation, adds toluene and stirs layering, collected organic layer; the organic layer washing; drying, underpressure distillation get 0.87kg oily compound 7, yield 50.4%.
Embodiment 14
The synthetic method of compound 8:
Add 0.7kg (1.213mol) compound 7, acetonitrile 10L in the 20L reactor, room temperature drips 1mol/L hydrochloric acid 1.5L, reaction 2h, and the TLC detection reaction is complete; Be cooled to 5 ℃, drip the 2L1mol/L sodium hydroxide solution, 10 ℃ of temperature controls, 30min drips off, reaction 1h, the TLC detection reaction is complete, is cooled to-5 ℃, slowly drip 1mol/L hydrochloric acid reaction solution pH is transferred to 3.4, temperature control-5 ℃ adds solid sodium chloride, stirs 10min, dissolving, separatory, the organic layer anhydrous magnesium sulfate drying adds 30% methylamine-ethanolic soln in the filtrate, 25 ℃ of reaction 3h, concentrating under reduced pressure removes 2/3 solvent, is cooled to 0 ℃, stirs 1h, suction filtration, the gained solid obtains the white solid methylamine salt at 45 ℃ of drying under reduced pressure;
In the 20L reactor, add 12L distilled water and methylamine salt solid, stir, add sodium hydroxide solution in the time of 15 ℃, 1h is carried out in reaction, drip calcium chloride water again, room temperature reaction 3h is cooled to 5 ℃, stirs 1h, suction filtration, the solid cold water washing gets the 0.427kg white solid at 40 ℃ of drying under reduced pressure, yield 70.3%.The purity of measuring rosuvastain calcium through high performance liquid phase is 99.5%.
Embodiment 15
The synthetic method of compd B:
In the 100mL reaction flask, add the 40mL1mol/L sodium hydroxide solution, be heated to 50 ℃, add 5.8g (11.72mmol) compd A, stirring reaction 5 hours is cooled to 0 ℃, dripping hydrochloric acid regulator solution PH to 3, stir, filter, dry cake obtains white solid, directly drops into the next step.
Embodiment 16
The synthetic method of compd B:
In the 100mL reaction flask, add the 40mL0.5mol/L sodium hydroxide solution, be heated to 40 ℃, add 5.8g (11.72mmol) compd A, stirring reaction 7 hours is cooled to 0 ℃, dripping hydrochloric acid regulator solution PH to 2, stir, filter, dry cake obtains white solid, directly drops into the next step.
Embodiment 17
The synthetic method of compd B:
In the 100mL reaction flask, add the 40mL2mol/L sodium hydroxide solution, be heated to 60 ℃, add 5.8g (11.72mmol) compd A, stirring reaction 3 hours is cooled to 0 ℃, dripping hydrochloric acid regulator solution PH to 4, stir, filter, dry cake obtains white solid, directly drops into the next step.
Embodiment 18
The synthetic method of Compound C:
In the 100mL reaction flask, add methylene dichloride 60mL, add 5g (10.4mmol) compd B and an amount of Anhydrous potassium carbonate, be heated to dissolving, add N-PROPYLE BROMIDE 5mL, back flow reaction 20h, 2/3 solvent is removed in underpressure distillation, be cooled to 5 ℃, stir 1h, filter, drying obtains white solid 5.0g, yield 91.92%.
Embodiment 19
The synthetic method of Compound C:
In the 100mL reaction flask, add methylene dichloride 60mL, add 5g (10.4mmol) compd B and an amount of Anhydrous potassium carbonate, be heated to dissolving, add N-PROPYLE BROMIDE 3.7mL, back flow reaction 15h, 2/3 solvent is removed in underpressure distillation, be cooled to 5 ℃, stir 1h, filter, drying obtains white solid 4.92g, yield 90.45%.
Embodiment 20
The synthetic method of Compound C:
In the 100mL reaction flask, add methylene dichloride 60mL, add 5g (10.4mmol) compd B and an amount of Anhydrous potassium carbonate, be heated to dissolving, add N-PROPYLE BROMIDE 6.5mL, back flow reaction 12h, 2/3 solvent is removed in underpressure distillation, be cooled to 5 ℃, stir 1h, filter, drying obtains white solid 5.15g, yield 94.62%.
Embodiment 21
The synthetic method of Compound C:
In the 100mL reaction flask, add methylene dichloride 60mL, add 5g (10.4mmol) compd B and an amount of Anhydrous potassium carbonate, be heated to dissolving, add 1-bromine normal butane 4.3mL, back flow reaction 20h, 2/3 solvent is removed in underpressure distillation, be cooled to 5 ℃, stir 1h, filter, drying obtains white solid 5.04g, yield 90.32%.
Embodiment 22
The synthetic method of Compound C:
In the 100mL reaction flask, add methylene dichloride 60mL, add 5g (10.4mmol) compd B and an amount of Anhydrous potassium carbonate, be heated to dissolving, add 1-bromine Skellysolve A 6.7mL, back flow reaction 20h, 2/3 solvent is removed in underpressure distillation, be cooled to 5 ℃, stir 1h, filter, drying obtains white solid 5.23g, yield 91.25%.
Embodiment 23
The synthetic method of Compound C:
In the 100mL reaction flask, add methylene dichloride 60mL, add 5g (10.4mmol) compd B and an amount of Anhydrous potassium carbonate, be heated to dissolving, add 1-iodine normal butane 6.5mL, back flow reaction 20h, 2/3 solvent is removed in underpressure distillation, be cooled to 5 ℃, stir 1h, filter, drying obtains white solid 5.32g, yield 92.8%.
Embodiment 24
Synthesizing of rosuvastain calcium:
Add 5.0g (9.56mmol) Compound C, acetonitrile 30mL in the 100mL reaction flask, room temperature drips 1mol/L sodium hydroxide 20mL, 20 ℃ of temperature controls, reaction 6h adds calcium acetate 4.17g, stirs 2 hours, is cooled to 0 ℃, filter cold water washing, the dry solid rosuvastain calcium 4.4g that gets.The gained Rosuvastatin reaches 99.8% through its purity of efficient liquid phase chromatographic analysis.
Embodiment 25
Synthesizing of rosuvastain calcium:
Add 5.0g (9.56mmol) Compound C, acetonitrile 30mL in the 100mL reaction flask, room temperature drips 1mol/L sodium hydroxide 20mL, 20 ℃ of temperature controls, reaction 6h adds calcium chloride 4.07g, stirs 2 hours, is cooled to 0 ℃, filter cold water washing, the dry solid rosuvastain calcium 4.37g that gets.The gained Rosuvastatin reaches 99.3% through its purity of efficient liquid phase chromatographic analysis.
Embodiment 26
Relax and to cut down the synthetic of his spit of fland calcium:
Add 5.0g (9.56mmol) Compound C, acetonitrile 30mL in the 100mL reaction flask, room temperature drips 1mol/L sodium hydroxide 20mL, 20 ℃ of temperature controls, reaction 6h adds nitrocalcite 4.23g, stirs 2 hours, is cooled to 0 ℃, filter cold water washing, the dry solid rosuvastain calcium 4.38g that gets.The gained Rosuvastatin reaches 99.5% through its purity of efficient liquid phase chromatographic analysis.
Claims (5)
1. the synthetic method of a rosuvastain calcium comprises the steps:
Described side chain is:
Wherein, R
1Be the cycloalkyl of the alkyl or 3-6 the carbon atom of 1-10 carbon atom, Z is-PPh
3 +Br
-Or-PO (OAk)
2Or-POAr
2, its Ak is the alkane of 1-4 carbon atom, Ar is the aromatic hydrocarbons of 6-8 carbon atom,
It is characterized in that, make compound 62,2,6, the following and branched chain reaction of the effect of 6-tetramethyl piperidine, n-Butyl Lithium, generate compound 7, the temperature that the chemical reaction of described compound 6 and side chain carries out is-25 ℃, described compound 6 and adding 2,2,6, the amount of substance ratio of 6-tetramethyl piperidine is 1: 4.5～5.5.
2. synthetic method according to claim 1 is characterized in that, described R
1Straight chained alkyl for 1-5 carbon atom.
3. synthetic method according to claim 1 is characterized in that, described compound 6 and adding 2,2,6, and the amount of substance ratio of 6-tetramethyl piperidine is 1: 4.5～5.0.
4. synthetic method according to claim 1 is characterized in that, described compound 6 is 1: 1.0～2.0 with the ratio of the amount of substance of side chain.
5. according to the described synthetic method of claim 4, it is characterized in that described compound 6 is 1: 1.0～1.5 with the amount of substance ratio of side chain.
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| CN2008101467326A CN101376647B (en) | 2007-08-31 | 2008-08-27 | Method for synthesizing rosuvastatin intermediate and rosuvastatin |
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| CN2008101467326A CN101376647B (en) | 2007-08-31 | 2008-08-27 | Method for synthesizing rosuvastatin intermediate and rosuvastatin |
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Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2725052C (en) | 2008-05-27 | 2014-09-16 | Changzhou Pharmaceutical Factory Co., Ltd. | Preparation method of rosuvastatin calcium and its intermediates |
| GB0904104D0 (en) * | 2009-03-10 | 2009-04-22 | Bradford Pharma Ltd | Atorvastatin and rosuvastatin derivatives |
| WO2012011129A2 (en) * | 2010-07-22 | 2012-01-26 | Msn Laboratories Limited | Novel polymorph of bis[(e)-7-[4-(4-fluorophenyl)-6-iso-propyl-2-[methyl (methylsulfonyl)amino]pyrimidin-5-yl](3r,5s)-3,5-dihydroxyhept-6-enoic acid] calcium salt |
| CN101955463B (en) * | 2010-08-04 | 2012-01-04 | 重庆博腾制药科技股份有限公司 | Method for preparing rosuvastatin calcium intermediate |
| CN102311457B (en) * | 2011-09-16 | 2014-04-16 | 苏州莱克施德药业有限公司 | Preparation method of rosuvastatin |
| CN103483269B (en) * | 2012-06-13 | 2016-04-27 | 上海迪赛诺药业有限公司 | The preparation method of rosuvastain calcium and intermediate thereof |
| CN103864697A (en) * | 2012-12-11 | 2014-06-18 | 润泽制药(苏州)有限公司 | Preparation method of rosuvastatin intermediate main chain alcohol |
| CN104230817B (en) * | 2013-06-19 | 2016-09-14 | 南京欧信医药技术有限公司 | The preparation method of 3,5-dihydroxy heptyl-6-gadoleic acid derivatives |
| CN103570762B (en) * | 2013-11-25 | 2015-12-09 | 复旦大学 | The preparation method of ((4-is to fluorophenyl-6-sec.-propyl-2-(N-methylmethanesulfonamide base)-5-pyridyl) methyl) triphenyl phosphonium salt |
| US9850213B2 (en) * | 2013-11-25 | 2017-12-26 | Jiangxi Boya Seehot Pharmaceutical Co., Ltd. | Method for preparing rosuvastatin sodium |
| CN103864698A (en) * | 2014-02-27 | 2014-06-18 | 常州金隆生物医药有限公司 | Method for preparing rosuvastatin calcium |
| CN103804414B (en) * | 2014-03-07 | 2016-04-13 | 凯莱英医药集团（天津）股份有限公司 | For the preparation of rosuvastain calcium midbody compound and prepared the method for rosuvastain calcium by it |
| CN104788387A (en) * | 2015-04-17 | 2015-07-22 | 浙江海森药业有限公司 | Preparation method for high-purity rosuvastatin calcium |
| CN105175346B (en) * | 2015-05-19 | 2018-02-06 | 上海弈柯莱生物医药科技有限公司 | A kind of method of synthesizing rosuvastatin spit of fland calcium intermediate |
| CN105037331B (en) * | 2015-06-17 | 2018-02-09 | 浙江科技学院 | The preparation method of Rosuvastatin intermediate |
| CN107445992A (en) * | 2017-06-19 | 2017-12-08 | 浙江美诺华药物化学有限公司 | A kind of synthetic method of Rosuvastatin Calcium intermediate |
| CN109824723A (en) * | 2017-11-23 | 2019-05-31 | 上虞京新药业有限公司 | A kind of rosuvastain calcium intermediate novel crystal forms |
| CN109824724A (en) * | 2017-11-23 | 2019-05-31 | 上虞京新药业有限公司 | A kind of preparation method of rosuvastain calcium intermediate |
| CN108707118A (en) * | 2018-06-22 | 2018-10-26 | 江苏阿尔法药业有限公司 | A kind of preparation method of demethyl rosuvastain calcium |
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