CN1958593A - Method for preparing intermediate of synthesizing rosuvastatin calcium - Google Patents
Method for preparing intermediate of synthesizing rosuvastatin calcium Download PDFInfo
- Publication number
- CN1958593A CN1958593A CN 200510110022 CN200510110022A CN1958593A CN 1958593 A CN1958593 A CN 1958593A CN 200510110022 CN200510110022 CN 200510110022 CN 200510110022 A CN200510110022 A CN 200510110022A CN 1958593 A CN1958593 A CN 1958593A
- Authority
- CN
- China
- Prior art keywords
- methyl
- pyrimidine
- fluorophenyl
- sec
- propyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
This invention discloses a method for preparing methyl (R)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-mesylamino)pyrimidin-5-yl]-3-tert-butyldimethylsiloxyl-5-carbonyl-6(E)-hepetnate as the intermediate for synthesizing rosuvastatin calcium. The method comprises: reducing pyrimidine carbonate (II) by borohydride/chloride to obtain pyrimidine methanol (III), oxidizing by potassium dichromate to obtain pyrimidine formaldehyde, and condensing in the presence of chiral phosphonate to obtain methyl (R)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-mesylamino)pyrimidin-5-yl]-3-tert-butyldimethylsiloxyl-5-carbonyl-6(E)-hepetnate (VI). The method has such advantages as abundant raw materials, low cost, mild reaction conditions, short time and high yield. The byproduct is water-soluble.
Description
Technical field
The present invention relates to a kind of intermediates preparation that is used for synthesizing rosuvastatin spit of fland calcium; specifically, relate to (R)-7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl]-preparation method of 3-(tertiary butyl dimethyl-silicon) oxygen base-5-carbonyl-6 (E)-heptenoic acid methyl esters.
Technical background
Rosuvastain calcium; chemical name two [(E)-7-[4-(4-fluorophenyl)-6-sec.-propyl-2-[methyl (methylsulfonyl) amino] pyrimidine-5-yl] (3R; 5S)-3; 5-dihydroxyl-6-heptenoic acid] calcium salt; it is the statins of new generation of complete synthesis single enantiomer; belong to the HMG-CoA reductase inhibitor, can reduce low density cholesterol, total cholesterol, triglyceride level and the apoB concentration of rising, simultaneously the concentration of increasing high density cholesterol.Can be used for the complex therapy of primary hypercholesterolemia and mixed type lipodystrophy disease and the familial hypercholesterolemia that isozygotys.Its structural formula is as follows:
(R)-7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl]-3-(tertiary butyl dimethyl-silicon) oxygen base-5-carbonyl-6 (E)-heptenoic acid methyl esters is the important intermediate of preparation rosuvastain calcium; U.S. Pat 5260440 discloses a kind of synthetic method of rosuvastain calcium; wherein; just relate to described intermediates preparation, the major defect of this technology is:
1, pyrimidine carbonic ether (II) the non-commercial reagent of reductive agent diisobutyl aluminium hydride of using when being reduced to alcohol, the source difficulty, and in-74 ℃ of reactions down, condition harshness;
2, rubigan (III) when being oxidized to aldehyde used oxygenant cross ruthenic acid tetrapropylammonium/N-methyl oxo morpholine difficulty of also originating.
3, aldehyde and chirality ylide condensation the reaction time are long, temperature height (80 ℃ were reacted 14 hours), and the TLC detection reaction is incomplete, needs the column chromatography purifying.
Therefore, above-mentioned 3 technology costs that increase U.S. Pat 5260440 disclosed technology greatly can not satisfy industrial requirement.
Summary of the invention
The technical issues that need to address of the present invention are to provide a kind of intermediates preparation that is used for synthesizing rosuvastatin spit of fland calcium, to overcome the defective that prior art exists.
Technical conceive of the present invention is such:
The present invention improves the content of following three aspects:
1, pyrimidine carbonic ether (II) is reduced in the reaction of alcohol, uses hydroborate/muriate as reductive agent.
2, rubigan (III) is oxidized in the reaction of aldehyde, uses potassium bichromate as oxygenant.
3, the condensation under alkaline condition, room temperature of an aldehyde and a chirality phosphonic acid ester (V) obtains (VI).
Method of the present invention specifically comprises the steps:
(1) preparation of [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl alcohol (III): the organic solution that will contain starting ester (II) adds and contains in hydroborate and the muriatic organic solution, 60~150 ℃ were reacted 0.5~5 hour, and collected pale solid [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl alcohol (III) from reaction product;
Said starting ester (II) can adopt U.S. Pat 5260440 disclosed methods to be prepared;
Said hydroborate is selected from a kind of in POTASSIUM BOROHYDRIDE, lithium borohydride or the sodium borohydride;
Said muriate is selected from a kind of in zinc chloride, aluminum chloride or the magnesium chloride;
Said organic solution is selected from 1,4-dioxane, diethylene glycol diethyl ether or tetrahydrofuran (THF);
Contain in the organic solution of starting ester (II), the concentration of starting ester (II) is 0.05~1.5mol/l;
The concentration that contains hydroborate in hydroborate and the muriatic organic solution is 0.2~5.0mol/l, and muriatic concentration is 0.1~2.5mol/l;
The organic solution that contains starting ester (II): contain hydroborate and muriatic organic solution=1: 0.02~100, volume ratio;
Reaction formula is as follows:
(2) preparation of [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] formaldehyde (IV): the dichloromethane solution that will contain in steps [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl alcohol (III) of (1); under 0~35 ℃; add the potassium bichromate and the vitriolic aqueous solution; reacted 0.5~5 hour; from reaction product, collect white solid [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] formaldehyde (IV) then, productive rate 93.2%.
In the methylene dichloride, the concentration of [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl alcohol (III) is 0.02~2mol/l, in the potassium bichromate and the vitriolic aqueous solution, the concentration of potassium bichromate is 0.02~2mol/l, and vitriolic concentration is 0.1~10mol/l;
Contain the methylene dichloride of [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl alcohol (III) of (1) in steps: the potassium bichromate and the vitriolic aqueous solution=1: 0.01~100, volume ratio; Reaction formula is as follows:
(3) (R)-7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl]-preparation of 3-(tertiary butyl dimethyl-silicon) oxygen base-5-carbonyl-6 (E)-heptenoic acid methyl esters (VI):
[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] formaldehyde (IV) with organic bases or mineral alkali adding step (2); (3R)-3-(tertiary butyl dimethyl-silicon) oxygen base-5-oxo-6-(dimethoxy) phosphinyl methyl caproate (V) and tetrahydrofuran (THF) mixing solutions; 0~100 ℃ of room temperature reaction 0.5~3 hour; from reaction product, collect target product (R)-7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl then]-3-(tertiary butyl dimethyl-silicon) oxygen base-5-carbonyl-6 (E)-heptenoic acid methyl esters (VI), productive rate: 69.9%.
Said organic bases or mineral alkali are selected from DBU, sodium hydride or salt of wormwood;
In the described mixing solutions, the concentration of [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] formaldehyde (IV) is 0.01~1mol/l, (3R)-concentration of 3-(tertiary butyl dimethyl-silicon) oxygen base-5-oxo-6-(dimethoxy) phosphinyl methyl caproate (V) is 0.01~1mol/l, the add-on of bases compound is with 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] molar weight of formaldehyde (IV) counts 50~500%;
Said (3R)-3-(tertiary butyl dimethyl-silicon) oxygen base-5-oxo-6-(dimethoxy) phosphinyl methyl caproate (V) can adopt J.org.chem, 1994,59; 7849-7854 document disclosed method is prepared, and the present invention repeats no more.
Reaction formula is as follows:
The another kind of preparation method of the present invention comprises the steps:
Alkali is joined [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] formaldehyde (IV), (3R)-3-(tertiary butyl dimethyl-silicon) oxygen base-5-oxo-6-(dimethoxy) phosphinyl methyl caproate (V) and acetonitrile mixing solutions; 0~100 ℃ of room temperature reaction 0.5~3 hour is collected target product (R)-7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl then from reaction product]-3-(tertiary butyl dimethyl-silicon) oxygen base-5-carbonyl-6 (E)-heptenoic acid methyl esters (VI).
The preparation method of [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] formaldehyde (IV); comprise the steps: to contain the dichloromethane solution of [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl alcohol (III); under 0~35 ℃; add the potassium bichromate and the vitriolic aqueous solution; reacted 0.5~5 hour, and from reaction product, collected white solid [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] formaldehyde (IV) then.
Said [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl alcohol (III) can adopt U.S. Pat 5260440 disclosed methods to be prepared;
In the methylene dichloride, the concentration of [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl alcohol (III) is 0.02~2mol/l, in the potassium bichromate and the vitriolic aqueous solution, the concentration of potassium bichromate is 0.02~2mol/l, and vitriolic concentration is 0.1~10mol/l;
The methylene dichloride that contains [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl alcohol (III): the potassium bichromate and the vitriolic aqueous solution=1: 0.01~100, volume ratio;
In the described mixing solutions; the concentration of [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] formaldehyde (IV) is 0.01~1mol/l; (3R)-concentration of 3-(tertiary butyl dimethyl-silicon) oxygen base-5-oxo-6-(dimethoxy) phosphinyl methyl caproate (V) is 0.01~1mol/l, the add-on of sodium hydride is with 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] molar weight of formaldehyde (IV) counts 50~500%.
Technology after the improvement has been compared following advantage with former technology:
1, with lithium borohydride/zinc chloride cheap and easy to get, avoided the use of expensive inflammable diisobutyl aluminium hydride, got rid of cold operation (74 ℃), the two yield is (91.8% pair 96.1%) quite.
2,, avoided expensive import reagent to cross ruthenic acid tetrapropylammonium and N-methyl oxo morpholine, and yield improve (93.2% pair 71.3%) greatly with potassium bichromate cheap and easy to get.
3, aldehyde and chiral phosphonate condensation reaction, the reaction conditions gentleness, the time is short, and the by product of generation is water-soluble, gets final product purifying by washing, need not column chromatography and purifies, and therefore, method of the present invention is more suitable for suitability for industrialized production.
Embodiment
Below in conjunction with specific embodiment the present invention is further described, but does not limit the present invention.
Embodiment 1
The preparation of [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl alcohol (III)
(2.8g 53.8mmol) joins 1, and in the 4-dioxane (50ml), (3.6g, 26.5mmol), 10 ℃ were stirred 2 hours to add the dry Zinc Chloride Anhydrous of crossing again with POTASSIUM BOROHYDRIDE.(5.0g 12.7mmol) is dissolved in 1, the solution of 4-dioxane (30ml) to drip starting ester (II).Be heated to 90 ℃ of reactions 2 hours, filter, filtrate concentrates the back and dilutes with ethyl acetate (50ml), and transferring to the pH value with 1N hydrochloric acid is 3, separatory, water layer extracts with ethyl acetate (20ml * 2), merge organic layer, be washed till neutrality with 10% sodium hydrogen carbonate solution, after the washing, concentrate a pale solid III4.1g, yield 91.8%.
Embodiment 2
The preparation of [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl alcohol (III)
(1.2g 54.5mmol) joins 1, and in the 4-dioxane (50ml), (3.5g, 26.2mmol), 35 ℃ were stirred 1.5 hours to add Aluminum chloride anhydrous again with lithium borohydride.(5.0g 12.7mmol) is dissolved in 1, the solution of 4-dioxane (30ml) to drip starting ester (II).Be heated to 80 ℃ of reactions 2 hours, filter, filtrate concentrates the back and dilutes with ethyl acetate, and it is 3 that dilute hydrochloric acid transfers to the pH value, separatory, the water layer ethyl acetate extraction merges organic layer, is washed till neutrality with 10% sodium hydrogen carbonate solution, washing, concentrate a pale solid III3.7g, yield 82.8%.
Embodiment 3
The preparation of [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl alcohol (III)
(2.8g 53.8mmol) joins in the diethylene glycol diethyl ether (50ml), and (3.6g, 26.5mmol), 25 ℃ were stirred 3 hours to add the dry Zinc Chloride Anhydrous of crossing again with POTASSIUM BOROHYDRIDE.(5.0g 12.7mmol) is dissolved in the solution of di-alcohol diethyl ether (30ml) to drip starting ester (II).Be heated to 150 ℃ of reactions 1 hour, filter, filtrate concentrates the back and dilutes with ethyl acetate, and it is 3 that dilute hydrochloric acid transfers to the pH value, separatory, the water layer ethyl acetate extraction, merge organic layer, be washed till neutrality with 10% sodium hydrogen carbonate solution, after the washing, concentrate the rear pillar chromatogram purification and get a white solid III2.4g, yield 53.7%.
Embodiment 4
The preparation of [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl alcohol (III)
(2.8g 53.8mmol) joins in the tetrahydrofuran (THF) (50ml), and (3.6g, 26.5mmol), 20 ℃ were stirred 1.2 hours to add the dry Zinc Chloride Anhydrous of crossing again with POTASSIUM BOROHYDRIDE.(5.0g 12.7mmol) is dissolved in the solution of tetrahydrofuran (THF) (30ml) to drip starting ester (II).Be heated to 60 ℃ of reactions 5 hours, filter, filtrate concentrates the back and dilutes with ethyl acetate, and transferring to the pH value with dilute hydrochloric acid is 3, separatory, the water layer ethyl acetate extraction, merge organic layer, be washed till neutrality with 10% sodium hydrogen carbonate solution, after the washing, concentrate the rear pillar chromatogram purification and get a white solid III2.0g, yield 44.8%.
Embodiment 5
The preparation of [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] formaldehyde (IV)
Intermediate ethanol (III) 4.1g (11.6mmol) is dissolved in the methylene dichloride (40ml), and under 30 ℃, (4.0g 13.6mmol)+solution of sulfuric acid (3ml)+water (30ml), drips and finishes, 30 ℃ of reactions 1 hour down to drip potassium bichromate.Add 10% sodium sulfite solution (30ml) in the reaction solution, separatory, water layer merges organic layer with methylene dichloride (30ml * 2) extraction, washes twice with water, concentrate behind the anhydrous sodium sulfate drying 3.8g white solid IV, productive rate 93.2%.
Embodiment 6
The preparation of [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] formaldehyde (IV)
Intermediate ethanol (III) 4.1g (11.6mmol) is dissolved in the methylene dichloride (40ml), and under 20 ℃, (1.4g 14.0mmol)+solution of sulfuric acid (3ml)+water (30ml), drips and finishes, 20 ℃ of reactions 1.2 hours to drip chromic oxide.Add 10% sodium sulfite solution, separatory, the water layer dichloromethane extraction merges organic layer, washing, dry concentrate 3.5g white solid IV, productive rate 85.8%.
Embodiment 7
The preparation of [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] formaldehyde (IV)
Intermediate ethanol (III) 4.1g (11.6mmol) is dissolved in the methylene dichloride (40ml), and under 0 ℃, (4.0g 13.6mmol)+solution of sulfuric acid (3ml)+water (30ml), drips and finishes, 0 ℃ of reaction 5 hours to drip potassium bichromate.Add 10% sodium sulfite solution, separatory, the water layer dichloromethane extraction merges organic layer, washing, the dry rear pillar chromatogram purification that concentrates gets 2.7g white solid IV, productive rate 66.2%.
Embodiment 8
The preparation of [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] formaldehyde (IV)
Intermediate ethanol (III) 4.1g (11.6mmol) is dissolved in the methylene dichloride (40ml), and under the room temperature, (4.0g 13.6mmol)+solution of sulfuric acid (3ml)+water (30ml), drips and finishes, 100 ℃ of reactions 30 minutes to drip potassium bichromate.Add 10% sodium sulfite solution, separatory, the water layer dichloromethane extraction merges organic layer, washing, the dry rear pillar chromatogram purification that concentrates gets 1.8g white solid IV, productive rate 44.1%.
Embodiment 9
(R)-7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl]-preparation of 3-(tertiary butyl dimethyl-silicon) oxygen base-5-carbonyl-6 (E)-heptenoic acid methyl esters (VI)
With intermediate aldehydes (IV) 3.8g (10.8mmol) and (3R)-3-(tertiary butyl dimethyl-silicon) oxygen base-5-oxo-6-(dimethoxy) phosphinyl methyl caproate (V) 4.1g (10.8mmol), tetrahydrofuran (THF) (20ml) mix, under 0 ℃, drip DBU (1.9g, 12.5mmol), finish, 0 ℃ was reacted 3 hours.Reaction solution is poured in the 20ml frozen water, is transferred to neutrality with 2N hydrochloric acid, ethyl acetate (30ml * 3) extraction, combining extraction liquid, washing, dry back concentrate the 4.6g light yellow oil, productive rate: 69.9%.
Embodiment 10
(R)-7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl]-preparation of 3-(tertiary butyl dimethyl-silicon) oxygen base-5-carbonyl-6 (E)-heptenoic acid methyl esters (VI)
With intermediate aldehydes (IV) 3.8g (10.8mmol) and (3R)-3-(tertiary butyl dimethyl-silicon) oxygen base-5-oxo-6-(dimethoxy) phosphinyl methyl caproate (V) 4.1g (10.8mmol), acetonitrile (20ml) mix, under 0 ℃, add sodium hydride (0.3g in batches, 12.5mmol), finish room temperature reaction 1 hour.Reaction solution is poured in the 20ml frozen water, is transferred to neutrality with 2N hydrochloric acid, ethyl acetate extraction, combining extraction liquid, washing, dry back concentrate the 3.7g light yellow oil, productive rate: 56.2%.
Embodiment 11
(R)-7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl]-preparation of 3-(tertiary butyl dimethyl-silicon) oxygen base-5-carbonyl-6 (E)-heptenoic acid methyl esters (VI)
With intermediate aldehydes (IV) 3.8g (10.8mmol) and (3R)-3-(tertiary butyl dimethyl-silicon) oxygen base-5-oxo-6-(dimethoxy) phosphinyl methyl caproate (V) 4.1g (10.8mmol), N, dinethylformamide (20m1) mixes, under 0 ℃, add Anhydrous potassium carbonate (1.8g in batches, 13.0mmol), finish, 100 ℃ were reacted 30 minutes.Reaction solution is poured in the 20ml frozen water, transferred to neutrality with 2N hydrochloric acid, ethyl acetate extraction, combining extraction liquid, washing, dry back concentrates the rear pillar chromatogram purification and gets the 2.5g light yellow oil, productive rate: 38.0%.
Embodiment 12
(R)-7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl]-preparation of 3-(tertiary butyl dimethyl-silicon) oxygen base-5-carbonyl-6 (E)-heptenoic acid methyl esters (VI)
With intermediate aldehydes (IV) 3.8g (10.8mmol) and (3R)-3-(tertiary butyl dimethyl-silicon) oxygen base-5-oxo-6-(dimethoxy) phosphinyl methyl caproate (V) 4.1g (10.8mmol), tetrahydrofuran (THF) (20ml) mix, under 0 ℃, add sodium hydride (0.3g in batches, 12.5mmol), finish, 60 ℃ were reacted 1 hour.Reaction solution is poured in the 20ml frozen water, transferred to neutrality with 2N hydrochloric acid, ethyl acetate extraction, combining extraction liquid, washing, dry back concentrates the rear pillar chromatogram purification and gets the 3.1g light yellow oil, productive rate: 47.1%.
Claims (10)
1. an intermediates preparation that is used for synthesizing rosuvastatin spit of fland calcium is characterized in that, comprises the steps:
(1) preparation of [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl alcohol (III): the organic solution that will contain starting ester (II) adds and contains in hydroborate and the muriatic organic solution, 60~150 ℃ were reacted 0.5~5 hour, and collected pale solid [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl alcohol (III) from reaction product;
Said hydroborate is selected from a kind of in POTASSIUM BOROHYDRIDE, lithium borohydride or the sodium borohydride;
Said muriate is selected from a kind of in zinc chloride, aluminum chloride or the magnesium chloride;
(2) preparation of [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] formaldehyde (IV): the dichloromethane solution that will contain in steps [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl alcohol (III) of (1), under 0~35 ℃, add the potassium bichromate and the vitriolic aqueous solution, reacted 0.5~5 hour, and from reaction product, collected white solid [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] formaldehyde (IV) then;
(3) (R)-7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl]-preparation of 3-(tertiary butyl dimethyl-silicon) oxygen base-5-carbonyl-6 (E)-heptenoic acid methyl esters (VI):
[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] formaldehyde (IV) that alkali is added step (2), (3R)-3-(tertiary butyl dimethyl-silicon) oxygen base-5-oxo-6-(dimethoxy) phosphinyl methyl caproate (V) and tetrahydrofuran (THF) mixing solutions, 0~100 ℃ of room temperature reaction 0.5~3 hour is collected target product (R)-7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl then from reaction product]-3-(tertiary butyl dimethyl-silicon) oxygen base-5-carbonyl-6 (E)-heptenoic acid methyl esters (VI);
Said alkali is selected from DBU, sodium hydride or salt of wormwood.
2. method according to claim 1 is characterized in that, the said organic solution of step (1) is selected from 1,4-dioxane, diethylene glycol diethyl ether or tetrahydrofuran (THF).
3. method according to claim 2 is characterized in that, contains in the organic solution of starting ester (II), and the concentration of starting ester (II) is 0.05~1.5mol/l;
The concentration that contains hydroborate in hydroborate and the muriatic organic solution is 0.2~5.0mol/l, and muriatic concentration is 0.1~2.5mol/l;
The organic solution that contains starting ester (II): contain hydroborate and muriatic organic solution=1: 0.02~100, volume ratio.
4. method according to claim 1; it is characterized in that; in the methylene dichloride; the concentration of [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl alcohol (III) is 0.02~2mol/l; in the potassium bichromate and the vitriolic aqueous solution; the concentration of potassium bichromate is 0.02~2mol/l, and vitriolic concentration is 0.1~10mol/l.
5. method according to claim 4; it is characterized in that; contain the methylene dichloride of [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl alcohol (III) of (1) in steps: the potassium bichromate and the vitriolic aqueous solution=1: 0.01~100, volume ratio.
6. method according to claim 1; it is characterized in that; in the described mixing solutions; the concentration of [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] formaldehyde (IV) is 0.01~1mol/l, (3R)-and the concentration of 3-(tertiary butyl dimethyl-silicon) oxygen base-5-oxo-6-(dimethoxy) phosphinyl methyl caproate (V) is 0.01~1mol/l.
7. method according to claim 6 is characterized in that, the add-on of alkali is with 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] molar weight of formaldehyde (IV) counts 50~500%.
8. intermediates preparation that is used for synthesizing rosuvastatin spit of fland calcium; it is characterized in that; comprise the steps: [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] formaldehyde (IV) with the alkali adding; (3R)-0~100 ℃ of reaction of 3-(tertiary butyl dimethyl-silicon) oxygen base-5-oxo-6-(dimethoxy) phosphinyl methyl caproate (V) and tetrahydrofuran (THF) mixing solutions 0.5~3 hour, from reaction product, collect target product (R)-7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl then]-3-(tertiary butyl dimethyl-silicon) oxygen base-5-carbonyl-6 (E)-heptenoic acid methyl esters (VI).
9. method according to claim 8; it is characterized in that; the preparation method of [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] formaldehyde (IV); comprise the steps: to contain the dichloromethane solution of [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl alcohol (III); under 0~35 ℃; add the potassium bichromate and the vitriolic aqueous solution; reacted 0.5~5 hour, and from reaction product, collected white solid [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] formaldehyde (IV) then.
10. method according to claim 9; it is characterized in that; in the methylene dichloride; the concentration of [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl alcohol (III) is 0.02~2mol/l; in the potassium bichromate and the vitriolic aqueous solution; the concentration of potassium bichromate is 0.02~2mol/l, and vitriolic concentration is 0.1~10mol/l
The methylene dichloride that contains [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl alcohol (III): the potassium bichromate and the vitriolic aqueous solution=1: 0.01~100, volume ratio;
In the described mixing solutions; the concentration of [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] formaldehyde (IV) is 0.01~1mol/l; (3R)-concentration of 3-(tertiary butyl dimethyl-silicon) oxygen base-5-oxo-6-(dimethoxy) phosphinyl methyl caproate (V) is 0.01~1mol/l, the add-on of alkali is with 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] molar weight of formaldehyde (IV) counts 50~500%.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN200510110022A CN1958593B (en) | 2005-11-03 | 2005-11-03 | Method for preparing intermediate of synthesizing rosuvastatin calcium |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN200510110022A CN1958593B (en) | 2005-11-03 | 2005-11-03 | Method for preparing intermediate of synthesizing rosuvastatin calcium |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1958593A true CN1958593A (en) | 2007-05-09 |
CN1958593B CN1958593B (en) | 2010-05-05 |
Family
ID=38070458
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN200510110022A Active CN1958593B (en) | 2005-11-03 | 2005-11-03 | Method for preparing intermediate of synthesizing rosuvastatin calcium |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN1958593B (en) |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7687660B2 (en) | 2007-04-18 | 2010-03-30 | Teva Pharmaceutical Industries Ltd. | Process for preparing intermediates of HMG-CoA reductase inhibitors |
US7851624B2 (en) | 2003-12-24 | 2010-12-14 | Teva Pharamaceutical Industries Ltd. | Triol form of rosuvastatin and synthesis of rosuvastatin |
CN101955463A (en) * | 2010-08-04 | 2011-01-26 | 重庆博腾制药科技股份有限公司 | Method for preparing rosuvastatin calcium intermediate |
US7884226B2 (en) | 2007-07-12 | 2011-02-08 | Teva Pharmaceutical Industries, Ltd. | Purification of rosuvatatin intermediate by thin film evaporation and chemical method |
CN102358747A (en) * | 2011-08-30 | 2012-02-22 | 浙江宏元药业有限公司 | Rosuvastatin calcium intermediate and method for preparing rosuvastatin calcium intermediate and rosuvastatin calcium |
CN101381281B (en) * | 2007-09-03 | 2012-07-04 | 上海医药工业研究院 | (S)-4-bromo-1,3-butanediol preparation method |
CN103044339A (en) * | 2012-10-15 | 2013-04-17 | 武汉市江润精细化工有限责任公司 | Preparation method of rosuvastatin calcium intermediate |
CN103497212A (en) * | 2013-09-25 | 2014-01-08 | 浙江科技学院 | Preparation method of rosuvastatin calcium intermediate |
CN105237482A (en) * | 2015-11-02 | 2016-01-13 | 广州先至饲料添加剂有限公司 | Synthetic method for 2-ethyl-4-amino-5-hydroxymethyl pyrimidine |
CN108191772A (en) * | 2017-12-28 | 2018-06-22 | 江苏悦兴医药技术有限公司 | The synthetic method of rosuvastain calcium intermediate impurities |
CN110963971A (en) * | 2019-12-13 | 2020-04-07 | 浙江工业大学 | Preparation method for synthesizing rosuvastatin calcium intermediate |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE69223603T2 (en) * | 1991-06-19 | 1998-04-09 | Shionogi Seiyaku Kk | OPTICALLY ACTIVE INTERMEDIATE PRODUCT AND THEIR PRODUCTION |
JP2648897B2 (en) * | 1991-07-01 | 1997-09-03 | 塩野義製薬株式会社 | Pyrimidine derivatives |
-
2005
- 2005-11-03 CN CN200510110022A patent/CN1958593B/en active Active
Cited By (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7851624B2 (en) | 2003-12-24 | 2010-12-14 | Teva Pharamaceutical Industries Ltd. | Triol form of rosuvastatin and synthesis of rosuvastatin |
US7964748B2 (en) | 2007-04-18 | 2011-06-21 | Teva Pharmaceutical Industries, Ltd. | Process for preparing intermediates of HMG-CoA reductase inhibitors |
US7687660B2 (en) | 2007-04-18 | 2010-03-30 | Teva Pharmaceutical Industries Ltd. | Process for preparing intermediates of HMG-CoA reductase inhibitors |
US7884226B2 (en) | 2007-07-12 | 2011-02-08 | Teva Pharmaceutical Industries, Ltd. | Purification of rosuvatatin intermediate by thin film evaporation and chemical method |
CN101381281B (en) * | 2007-09-03 | 2012-07-04 | 上海医药工业研究院 | (S)-4-bromo-1,3-butanediol preparation method |
EP2602250A1 (en) * | 2010-08-04 | 2013-06-12 | Porton Fine Chemicals Ltd | Method for preparing rosuvastatin calcium intermediate |
CN101955463A (en) * | 2010-08-04 | 2011-01-26 | 重庆博腾制药科技股份有限公司 | Method for preparing rosuvastatin calcium intermediate |
WO2012016479A1 (en) * | 2010-08-04 | 2012-02-09 | 重庆博腾制药科技股份有限公司 | Method for preparing rosuvastatin calcium intermediate |
EP2602250A4 (en) * | 2010-08-04 | 2014-02-26 | Porton Fine Chemicals Ltd | Method for preparing rosuvastatin calcium intermediate |
JP2013532693A (en) * | 2010-08-04 | 2013-08-19 | 重▲慶▼博▲騰製薬▼科技股▲フン▼有限公司 | Method for preparing rosuvastatin calcium intermediate |
CN102358747B (en) * | 2011-08-30 | 2012-09-19 | 浙江宏元药业有限公司 | Rosuvastatin calcium intermediate and method for preparing rosuvastatin calcium intermediate and rosuvastatin calcium |
CN102358747A (en) * | 2011-08-30 | 2012-02-22 | 浙江宏元药业有限公司 | Rosuvastatin calcium intermediate and method for preparing rosuvastatin calcium intermediate and rosuvastatin calcium |
CN103044339A (en) * | 2012-10-15 | 2013-04-17 | 武汉市江润精细化工有限责任公司 | Preparation method of rosuvastatin calcium intermediate |
CN103497212A (en) * | 2013-09-25 | 2014-01-08 | 浙江科技学院 | Preparation method of rosuvastatin calcium intermediate |
CN103497212B (en) * | 2013-09-25 | 2015-11-18 | 浙江科技学院 | A kind of preparation method of rosuvastain calcium intermediate |
CN105237482A (en) * | 2015-11-02 | 2016-01-13 | 广州先至饲料添加剂有限公司 | Synthetic method for 2-ethyl-4-amino-5-hydroxymethyl pyrimidine |
CN108191772A (en) * | 2017-12-28 | 2018-06-22 | 江苏悦兴医药技术有限公司 | The synthetic method of rosuvastain calcium intermediate impurities |
CN110963971A (en) * | 2019-12-13 | 2020-04-07 | 浙江工业大学 | Preparation method for synthesizing rosuvastatin calcium intermediate |
CN110963971B (en) * | 2019-12-13 | 2021-10-15 | 浙江工业大学 | Preparation method for synthesizing rosuvastatin calcium intermediate |
Also Published As
Publication number | Publication date |
---|---|
CN1958593B (en) | 2010-05-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1958593A (en) | Method for preparing intermediate of synthesizing rosuvastatin calcium | |
CN100351240C (en) | Rosuvastatin calcium synthesis method | |
CN1884263A (en) | Pregabalin intermediate and process for preparing same | |
CN101058557A (en) | Method of preparing polyhydroxy annular nitrone | |
CN1561341A (en) | Hydrolysis of [R(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid esters with calcium hydroxide | |
CN1821242A (en) | Novel method for preparing dihydroxy acid HMG CoA reductase inhibitor | |
CN1805926A (en) | Process for the preparation of trans-isomers of diphenylazetidinone derivatives | |
CN1876613A (en) | (E)-3,5-dimethox-4'-hydroxy diphenyl ethylene synthesis method | |
CN1321114C (en) | Orlistat preparation method | |
CN1109023C (en) | Preparation of pyrimidine derivatives | |
CN101050217A (en) | Method for synthesizing Vardenafil hydrochloric acid | |
CN1942422A (en) | Method for producing hydrate of fluoroalkyl ketone | |
CN1891807A (en) | Guerbet anionic surfactant and preparation method and application thereof | |
CN1266155C (en) | 6-chloro-4-hydroxy-2-methyl-2H-thieno-(2,3-e)-1,2-thiazine-1,1-dioxide-3 | |
CN1834093A (en) | Synthesis method of chiral 2-amino-1- (6-fluoro-3, 4-dihydrobenzopyranyl) ethanol | |
CN1876644A (en) | (4R-cis)-6-formyl-2,2-dimethyl-1,3- dioxane -4- tertiary butyl acetate synthesis method | |
CN1821220A (en) | Diethyl 4[(4-oxo-3-bromo) butyl] benzoyl-L-glutamate and preparation and use | |
CN1903833A (en) | Method of preparing tuoteludin and its L-tartarate | |
CN101892276B (en) | Atorvastatin calcium compound and new method thereof | |
CN1721419A (en) | Process for synthesizing dithio ketene condensate in aqueous medium | |
CN1974553A (en) | Prepn process of Ropinirole and its derivative | |
CN1279035C (en) | Synthesis method of optical enantiomer 6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-carboxylic acid and 6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-carboxylic ester | |
CN1093853C (en) | New method for preparing (S)-4-amino-hepta-5,6-dienoic acid and intermediate thereof | |
CN1505622A (en) | Method for producing (dioxolenon-4-yl)methyl ester derivative | |
CN1304373C (en) | Method for preparing aripiprazole and its intermediate |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
EE01 | Entry into force of recordation of patent licensing contract |
Assignee: Nanjing Chia Tai Tianqing Pharmaceutical Co., Ltd. Assignor: Shanghai Institute of pharmaceutical industry Contract record no.: 2011320001123 Denomination of invention: Method for preparing intermediate of synthesizing rosuvastatin calcium Granted publication date: 20100505 License type: Exclusive License Open date: 20070509 Record date: 20110927 |