CN109574830A - A kind of rosuvastain calcium intermediate and its preparation method and application - Google Patents
A kind of rosuvastain calcium intermediate and its preparation method and application Download PDFInfo
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- CN109574830A CN109574830A CN201910006754.0A CN201910006754A CN109574830A CN 109574830 A CN109574830 A CN 109574830A CN 201910006754 A CN201910006754 A CN 201910006754A CN 109574830 A CN109574830 A CN 109574830A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07C67/00—Preparation of carboxylic acid esters
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- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07D239/42—One nitrogen atom
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- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract
The invention discloses a kind of rosuvastain calcium intermediates and its preparation method and application, and the intermediate synthesis technology is environmental-friendly, easy to operate, EHS risk is low, and raw material is easy to get, chemical reagent small toxicity used, it is cheap, it is suitable for the green synthesis process of industrialized production.Moreover, intermediate provided by the invention is applied to the synthesis of rosuvastain calcium and its key intermediate, route is shorter, high income, significantly reduces the industrialized production cost of rosuvastain calcium, prospects for commercial application with higher.
Description
Technical field
The invention belongs to organic syntheses and field of pharmaceutical chemistry technology, and in particular to a kind of rosuvastain calcium intermediate and
Preparation method and application.
Background technique
Rosuvastain calcium, chemical name: bis- [(E) -7- [4- (4- fluorophenyl) -6- isopropyl -2- [(N- methyl-N- methylsulphurs
Acyl group) amido] pyrimidine -5- base] (3R, 5S) -3,5- dihydroxy -6- heptenoic acid] calcium salt is opened by Yan Yeyi company of Japan's research
Hair, and successfully realize that commercialized a HMG CoA (HMG-CoA) restores by AstraZeneca drugmaker, Britain
Enzyme inhibitor.2 months 2003, rosuvastain calcium was for the first time in the granted listing of Canada, for adult hypercholesterolemia and height
The treatment of blood lipid；In December, 2007, rosuvastain calcium obtains the approval of CFDA, into Chinese pharmaceutical control and administration market.Currently, auspicious relax is cut down
Statin calcium is in global more than 30 a granted listings in countries and regions, global marketing total value highest up to more than 70 hundred million U.S. dollars.
Due to the huge market prospects of rosuvastain calcium imitation medicine, global scientific research institution and drugmaker are to its technique
Develop also many, patent up to 90 remainders in terms of the rosuvastain calcium medicine synthesising process that can be inquired at present.To the greatest extent
The pipe prior art has largely reported the synthesis of rosuvastain calcium, but classical Wittig reaction is still that current building is female
The synthetic method for the carbon-carbon double bond mainstream that core is connect with side chain is also suitable for the mainstream production technology of industrialized production.
Rosuvastatin is described for the first time in the basic compound patent EP0521471 that Shionogi was submitted in 1992
The form of acid and its pharmaceutically acceptable salt, and disclose its synthetic method.The synthetic method is work when compound is found
Skill, route is tediously long, complex steps, and multiple oxidation reaction causes the yield of integrated artistic relatively low, is not suitable for industrialization.
Later development quotient AstraZeneca has carried out a large amount of optimizations and adjustment to the synthesis technology of rosuvastain calcium, at it
In the patent WO00049014 submitted for 1999, it was recently reported that using diphenyl phosphine oxide as parent nucleus, in two (trimethyl silicane of highly basic
Base) stable phosphorus ylide reagent is formed under the action of amido potassium (KHMDS), it Wittig occurs with side chain D-7 reacts to be made auspicious
It relaxes and cuts down the main structure of statin calcium, shown in following scheme one.Because stable phosphorus ylide reagent contributes to form E type product,
So the carbon-carbon double bond E/Z constructed in the reaction process selectively up to 95% or more.The technique becomes first realization industrialization
Technique, but since side chain aldehyde D-7 is poor in basic conditions stability inferior, so, the yield of entire route is relatively low.In addition, making
The price of highly basic two (trimethyl silicon substrate) amido potassium is higher, also further results in the synthesis technology cost increase.But due to
The synthesis technology constructs the carbon-carbon double bond E/Z selectivity height between parent nucleus and side chain, still has a large amount of companies using the route at present
Prepare Rosuvastatin calcium raw material drug.
Scheme one
Glenmark company reports in patent WO2005054207 replaces organic phosphonate reagent (such as triphenylphosphine, etc.) to use
In the phosphonium salt for preparing pyrimidine parent nucleus, and is reacted through Wittig with side chain aldehyde D-7, be deprotected, hydrolyze and be made auspicious at processes such as salt
It relaxes and cuts down statin calcium, shown in following scheme two.In the synthetic route of the patent report, substrate Wittig reaction in building parent nucleus with
Carbon-carbon double bond E/Z between side chain is selectively relatively low, but technique entirety yield is higher, totle drilling cost is lower so that the synthetic route at
For the mainstream industry metaplasia production. art being the most widely used at present.
Scheme two
In the industrialized producing technology of existing mainstream, side chain D-7 is must in Rosuvastatin calcium raw material drug synthesis process
The key intermediate that must be used.Since its usage amount is big, the market demand is more, a large amount of texts existing to the research of the synthetic method of D-7
Offer report.As reported in patent US5278313, WO0185975, WO2012130919, WO0206266, WO03053950
The novel synthesis of D-7, but the technique that can be realized industrialization in the prior art is then less.
AstraZeneca discloses the industrialization synthetic route of side chain D-7, following three institute of scheme in patent WO-00206266
Show.The process route is tediously long, and has used the disagreeableness chemical reagent of environment, such as bromine, tetrabutyl ammonium acetate salt.Bromine peace
Full hidden danger is big, and environment is unfriendly；Cost for wastewater treatment containing tetrabutyl ammonium fluoride is high；The activity secondly as chlorine atom is left away
It is poor, high temperature (100 DEG C or more), for a long time reaction are needed in the step of chlorine atom is converted into acetoxyl group, this further gives work
Skill increases unfriendly property, and technique entirety yield is relatively low, product appearance is partially yellow.
Scheme three
The technique that the Blaise that reports in patent WO2014203045, CN101613341 is reacted for constructing side chain is also
The D-7 industrializing synthesis route being the most widely used at present, shown in following scheme four.But there are still a large amount of deficiencies for the technique, such as
Process route is tediously long, and the reaction that chlorine atom is converted into acetoxyl group needs high temperature (100 DEG C or more), reacts for a long time, gives technique
Increase unfriendly property.And since long-time pyroreaction causes product appearance color deeper, post-processing is cumbersome, and technique is whole
Body yield is also relatively low.The technique has still used the poisonous reagent Cymag of the art, not only constitutes to human health very big
Harm, and would seriously pollute the environment, it is EHS greater risk source in commercial process.It is also used in the technique organic
Amine salt increases the processing difficulty and cost of nitrogenous effluent.
Scheme four
Numerous deficiencies based on the D-7 prior art are developed more environmentally friendly green synthesis process for three wastes emission reduction, are reduced
EHS risk in production process, it appears particularly important.The present invention provides a kind of new method of D-7 synthesis, the novel synthesis
Raw material is easy to get, chemical reagent small toxicity used, cheap, and process environments are friendly, and easy to operate, EHS risk is low, is suitable for
The green synthesis process of industrialized production.Moreover, technique provided by the invention effectively shortens the synthesis step of D-7, improve
The total recovery of rosuvastain calcium synthesis, significantly reduces production cost.
Summary of the invention
The present invention provides a kind of new rosuvastain calcium intermediate and preparation method thereof, and the present invention also provides a kind of systems
The new technology route of standby rosuvastain calcium key intermediate D-7, the technological reaction is mild, EHS risk is low, easy to operate, ring
Border close friend, high income, are suitable for the friendly process of industrialized production.
A kind of intermediate of rosuvastain calcium, which is characterized in that structure is as shown in formula I:
The present invention also provides a kind of methods for preparing type I compound, which comprises the steps of:
II compound of step A. formula is reacted with metal M, forms organometallic reagent；
Organometallic reagent obtained by step B.A step and CH3COOCH2COCl reacts to obtain type I compound.
Wherein, X independently is halogen atom, is selected from Cl, Br, I, preferably Br；M is metal, preferably magnesium and zinc；
Specifically, heretofore described method, which is characterized in that the reaction in step A is preferably in the ethers of reflux
It is carried out in solvent, including but not limited to ether, tetrahydrofuran, 2- methyltetrahydrofuran.
Specifically, heretofore described method, which is characterized in that the molar ratio of formula II compound and metal M
For 1:1~1:1.5, preferably 1:1.2~1:1.3.
More specifically, heretofore described method, which is characterized in that II compound of formula and reagent C H3COOCH2COCl
Molar ratio be 1:1~1:5, preferably 1:2~1:3.
Further, the present invention also provides a kind of applications of type I compound, which is characterized in that the type I compound
Synthesis for III compound of formula.
Further, application of the heretofore described type I compound in the calcium of synthesizing rosuvastatin spit of fland.
Specifically, heretofore described application, which is characterized in that the conversion of type I compound to III compound of formula can
It is realized using chemical reduction method, the realization of enzyme process restoring method can also be used.
More specifically, heretofore described application, which is characterized in that reducing agent used in reduction method process is selected from
Boron hydride, chiral borane derivative, aluminium isopropoxide, dicarbapentaborane reductase, preferably dicarbapentaborane reductase.
It requires emphasis and illustrates, during II preparation of compounds of formula of formula, I compound, organometallic reagent is preferably logical
The mode being added dropwise is crossed to be added to reagent C H3COOCH2In COCl.Keep CH3COOCH2The excess of COCl reagent can effectively reduce pair
The generation of reaction improves the yield of type I compound.But simultaneously it is emphasized that the mistake of II preparation of compounds of formula of formula, I compound
Step A " one kettle way " synchronous with step B completion may be implemented for certain substrates in Cheng Zhong.The present invention research has shown that, charging
Sequence makes a significant impact the yield of product, and the present invention has passed through preferred embodiment and verified.Any pair of formula II is changed
The adjustment of charging sequence is accordingly to be regarded as being included within the present invention during conjunction object preparation type I compound.
It needs further exist for emphasizing and illustrate, the application that the present invention provides type I compound is mainly used for Rosuvastain
The synthesis of spit of fland calcium raw material drug and its key intermediate D-7.Type I compound is protected by electronation or enzymatic reduction, acetonylidene
Protect to obtain compound D-5, the D-5 synthesis through deacetylation, oxidation realization D-7 again.Heretofore described chemical reduction method, also
Former agent boron hydride, including but not limited to lithium borohydride, sodium borohydride, potassium borohydride, calcium borohydride；Chiral borane derivative,
Including but not limited to chiral oxazaborolidine, chiral hydrocarbon groups borine.Heretofore described dicarbapentaborane reductase is a kind of with vertical
The biological enzyme of body specificity is able to achieve the synchronization Stereoselective reduction of two carbonyls in type I compound, has efficient, green
The characteristic of environmental protection.Different reducing agents will lead to different stereoselectivities, to influence the yield of reaction.The present invention by compared with
Good embodiment is shown that result of study shows only generate different stereoselectivity and receipts using different reducing agents
Rate difference, so, which is not limited to the reducing agent that the present invention has shown that, all pairs of carbonyls have the reagent of reproducibility
It will be apparent to those skilled in the art, the preferably environmentally protective dicarbapentaborane reductase of the present invention is reacted in the step
In application.
It should be noted that the present invention is compared with prior art, there is following clear superiority:
(1) use using hypertoxic chemical reagent Cymag is avoided in technique of the present invention；
(2) reaction condition is mild in technique of the present invention, avoids prolonged pyroreaction, reduces EHS wind
Danger, product appearance, quality and yield various aspects are superior to the prior art；
(3) raw material is easy to get in technique of the present invention, and route is short: preferred embodiment totally 6 step of synthesis D-7 of the present invention
Chemical reaction；Totally 8 steps chemically react existing industrialization technology synthesis D-7, shorten 2 steps；
(4) the technique three wastes of the present invention are few, and process condition is friendly, and total recovery is high, meet the spy of Green Chemistry
Sign: the preferred embodiment total recovery of synthesis D-7 of the present invention is 82.0%；Existing industrialization technology synthesizes D-7 total recovery
70.9%.
Term:
Heretofore described " EHS " refers to the abbreviation of environment Environment, health Health, safe Safety.
EHS policy is statement of the enterprise to the principle and intention of its whole environment, career safety & health behavior, embodies enterprise in ring
Border, the general direction of career safety & health protection aspect and fundamental commitment.The target indicator of EHS management system is for important ring
Factor that border factor, great risk factor or needs control and the quantified controlling index formulated.
Heretofore described " organometallic reagent " refers to be connected directly bonding with carbon atom and is formed by metallic atom
Organic compound, including but not limited to Grignard Reagent (halogenated organic matters are formed with magnesium metal), organic zinc reagent be (halogenated organic
Object and metallic zinc are formed), organic copper reagent (halogenated organic matters and metallic copper are formed), etc..And organic matter is formed with metal ion
Salt or within the scope of alkali is not included in this, such as sodium acetate (CH3COONa), sodium ethoxide (CH3CH2ONa), etc..
Heretofore described " one kettle way " refers to that in organic chemical reactions, all raw materials for participating in reaction are synchronous to be added
Into reactor, the mode of the intermediate of formation without isolation synthesizes a kind of synthetic method of target product.
Specific embodiment
It is of the invention can to make those skilled in the art comprehensive understanding for specific embodiment below, but does not limit this in any way
Invention.
In the examples below that, unless otherwise specified, all temperature are Celsius temperature；Unless otherwise specified, the room
Temperature is 20~30 DEG C；Unless otherwise specified, various starting materials and reagent are all from commercially available, without further purification directly
It uses；Unless otherwise specified, various solvents are technical grade solvent, are not used directly after further treatment；Unless otherwise specified,
Commercially available producer includes but is not limited to Hangzhou chemical reagent, traditional Chinese medicines reagent etc..
Embodiment 1:[2- chloromethyl-[1,3]-dioxolane -2- base] tert-butyl acetate preparation
50.0 grams of chloroacetyl tert-butyl acetates (1.0eq), 35.5g ethylene glycol (2.2eq) are added to 500mL three-neck flask
In.Mixture stirs after ten minutes, is added 5.0g methane sulfonic acid (0.2eq), after being stirred at room temperature 3 hours, then is warming up to 50~60
DEG C stirring 3 hours.TLC monitors end of reaction, and reaction solution is cooled to room temperature, and 150mL saturated sodium bicarbonate solution condition water is added
Phase pH is 7~8.The extraction of 2 × 150mL ethyl acetate, gained ethyl acetate layer merge, and 40-50 DEG C is concentrated under reduced pressure to obtain light yellow liquid
Body 59.8g, yield 97.3%.ESI-MS:m/z238.52 [M+H]+；1H-NMR(CD3Cl, 400MHz): δ 3.96-4.12 (m,
4H),3.56(s,2H),2.48(s,2H),1.36(s,9H)；13C-NMR(CD3Cl, 125MHz): δ 172.3,122.1,80.6,
65.1,65.1,46.8,38.0,27.8,27.7,27.6。
Embodiment 2:[2- bromomethyl-[1,3]-dioxolane -2- base] tert-butyl acetate preparation
50.0 grams of bromoacetyl tert-butyl acetates (1.0eq), 28.9g ethylene glycol (2.2eq) are added to 500mL three-neck flask
In.Mixture stirs after ten minutes, is added 4.1g methane sulfonic acid (0.2eq), after being stirred at room temperature 3 hours, then is warming up to 50~60
DEG C stirring 3 hours.TLC monitors end of reaction, and reaction solution is cooled to room temperature, and 100mL saturated sodium bicarbonate solution condition water is added
Phase pH is 7~8.The extraction of 2 × 150mL ethyl acetate, gained ethyl acetate layer merge, and 40~50 DEG C are concentrated under reduced pressure to obtain yellow liquid
58.1g, yield 98.0%.ESI-MS:m/z282.05 [M+H]+；1H-NMR(CD3Cl, 400MHz): δ 3.94-4.08 (m, 4H),
3.52(s,2H),2.45(s,2H),1.37(s,9H)；13C-NMR(CD3Cl, 125MHz): δ 172.6,122.3,81.2,63.1,
63.1,38.6,31.8,27.8,27.7,27.6。
Embodiment 3: the preparation of acetoxy acetyl chloride
In 500mL three-necked bottle, 30.0g hydroxyacetic acid and 150mL methylene chloride are sequentially added, gained is molten after ten minutes for stirring
Liquid is cooled to 0~10 DEG C, sequentially add 44.3g acetic anhydride (1.1eq) and 2.4g N, N- dimethylamino naphthyridine (DMAP,
0.05eq).Reaction mixture stirs 4 hours after being warming up to room temperature.2 × 100mL 0.05N dilute hydrochloric acid solution washing reaction is added
Liquid, the methylene chloride organic layer after washing are concentrated to dryness in 40~50 DEG C.
Gained slurry 150mL methylene chloride dissolves, and lysate is transferred in 500mL three-necked bottle, adds 150 μ L
N,N-dimethylformamide (DMF).Under room temperature, 60.2g oxalyl chloride is gradually dropped into gained reaction mixture
(1.2eq).After being added dropwise, it is stirred at room temperature 3 hours.Reaction solution is concentrated to dryness to obtain solid product in 35~40 DEG C, standby
With.
Embodiment 4:6- acetoxy-3, the preparation of 5- dioxo-hecanoic acid t-butyl ester (I)
In step A:500mL three-neck flask, 1.02g magnesium chips (1.2eq), 0.03 gram of iodine, 100mL tetrahydrofuran are sequentially added
With 10.0g [2- bromomethyl-[1,3]-dioxolane -2- base] tert-butyl acetate (1.0eq), mixture, which is stirred to iodine, to be dissolved.It is mixed
It closes object and is warming up to 50~60 DEG C, 0.2 gram of bromoethane is slowly added dropwise.After reaction starting, 50~60 DEG C of reaction temperature are controlled, keeps four
It hydrogen tetrahydrofuran solution slightly boiled 1~2 hour, until magnesium chips disappears substantially, obtains Dark grey suspension and is cooled to room temperature, it is spare.
In the three-neck flask of step B:500mL, 9.7 grams of acetoxy acetyl chlorides (2.0eq), 80mL tetrahydro furan are sequentially added
It mutters.After ten minutes, mixture is cooled to -10~0 DEG C for stirring, and gained Dark grey suspension in step A is slowly added dropwise.After 2 hours
It is added dropwise, reaction mixture, which is warming up to, to be stirred at room temperature 3~4 hours.Reaction solution is cooled to 0~10 DEG C, to cooling after reaction solution
Middle dropwise addition saturated ammonium chloride solution quenching reaction, and stirring makes complete hydrolysis of ketal in 1 hour.Reaction solution after being quenched is added 2 ×
The extraction of 200mL methylene chloride.Merge dichloromethane layer extracted, 35~45 DEG C are concentrated under reduced pressure to obtain weak yellow liquid 8.32g, receive
Rate 90.6%.ESI-MS:m/z 259.33 [M+H]+；1H-NMR(CD3Cl, 400MHz): δ 5.23 (s, 2H), 3.94-4.08 (m,
4H),2.21(s,3H),1.37(s,9H)；13C-NMR(CD3Cl, 125MHz): δ 207.0,203.1,172.6,168.4,80.5,
73.0,70.6,48.8,27.8,27.7,27.6,21.3。
Embodiment 5:6- acetoxy-3, the preparation of 5- dioxo-hecanoic acid t-butyl ester (I)
In step A:500mL three-neck flask, 1.32g magnesium chips (1.3eq), 0.03 gram of iodine, 100mL tetrahydrofuran are sequentially added
With 10.0g [2- chloromethyl-[1,3]-dioxolane -2- base] tert-butyl acetate (1.0eq), mixture, which is stirred to iodine, to be dissolved.It is mixed
It closes object and is warming up to 50~60 DEG C, 0.2 gram of bromoethane is slowly added dropwise.After reaction starting, 50~60 DEG C of reaction temperature are controlled, keeps four
It hydrogen tetrahydrofuran solution slightly boiled 1~2 hour, until magnesium chips disappears substantially, obtains Dark grey suspension and is cooled to room temperature, it is spare.
In the three-neck flask of step B:500mL, 17.3g acetoxy acetyl chloride (3.0eq), 80mL tetrahydro furan are sequentially added
It mutters.After ten minutes, mixture is cooled to -10~0 DEG C for stirring, and gained Dark grey suspension in step A is slowly added dropwise.After 2 hours
It is added dropwise, reaction mixture is warming up to 30~40 DEG C and stirs 3~4 hours.Reaction solution is cooled to 0~10 DEG C, to cooling after it is anti-
It answers and saturated ammonium chloride solution is added dropwise in liquid.Reaction solution after being quenched stirs 1 hour, after TLC monitors contracting copper complete hydrolysis, is added 2
The extraction of × 200mL methylene chloride.Merge dichloromethane layer extracted, 35~45 DEG C are concentrated under reduced pressure to obtain weak yellow liquid 10.2g,
Yield 93.2%.
Embodiment 6:6- acetoxy-3, the preparation of 5- dioxo-hecanoic acid t-butyl ester (I)
In step A:500mL three-necked bottle, 150mL tetrahydrofuran, 3.5 grams of zinc powders (1.5eq), 6.4 grams of front threes are sequentially added
Base chlorosilane (1.65eq) stirs mixture and is warming up to 60~65 DEG C and flows back 3~4 hours.Then delay into reaction mixture
Slowly 10.0g [2- bromomethyl-[1,3]-dioxolane -2- base] tert-butyl acetate (1.0eq) is added dropwise into system.It is dripped after 2 hours
Add it is complete, keep reaction system slight boiling condition react 2~3 hours, obtain grey suspension, it is spare.
It in step B:500mL three-necked bottle, is added 14.6g acetoxy acetyl chloride (3.0eq), 100mL tetrahydrofuran, stirring
0~10 DEG C is cooled to after dissolved clarification, to cooling after grey suspension obtained by a dropping step A in reaction solution.It is warming up to after being added dropwise
30~40 DEG C are stirred 3~4 hours.Reaction solution is cooled to 0~10 DEG C, to cooling after saturated ammonium chloride solution is added dropwise in reaction solution.
Reaction solution after being quenched stirs 1 hour, and after TLC monitors contracting copper complete hydrolysis, the extraction of 2 × 200mL methylene chloride is added.Merge extraction
Dichloromethane layer after taking, 35~45 DEG C are concentrated under reduced pressure to obtain weak yellow liquid 8.7g, yield 94.6%.
Embodiment 7:(3R, 5S) -6- acetoxy-3,5- dihydroxy hecanoic acid t-butyl ester (III) preparation
Type I compound (10.0g, 38.8mmol) and 100mL DMF, stirring and dissolving are added in 500mL three-neck flask.In 1L
It is 500mL that reaction system is controlled in shaking flask, and the MOPS buffer solution after being sterilized with 200mL suspends and has aldehyde ketone reductase activity
The full cell of genetic engineering bacterium puts into glucose dehydrogenase, the NADP+ of the glucose 45mL, 0.25g of 2.5mol/L is added, will be molten
There is the DMF solution of type I compound to be poured slowly into shaking flask, the amount of the investment full cell of ketoreductase genetic engineering bacterium is 60g/L, is thrown
The amount for entering glucose dehydrogenase is 25mg/L, and the temperature for controlling transformation system is 25 DEG C, pH 6.5；Conversion reaction is in shaking table
It carries out, the revolving speed control of shaking table is 200r/min, transformation time 12h.TLC is monitored after completion of the reaction, and reaction solution is heated to 40
~50 DEG C of quenching reactions.Diatomite filters enzyme residue, and the extraction of 3 × 200mL ethyl acetate is added in filtrate, and merging extraction three times has
Machine phase, 35~45 DEG C are concentrated under reduced pressure to obtain yellow slurry 9.76g, yield 96.1%.ESI-MS:m/z 263.15 [M+H]+；1H-
NMR(CD3Cl, 400MHz): δ 5.01 (br s, 2H), 4.18-4.31 (m, 2H), 3.80-3.86 (m, 2H), 2.51-2.47 (m,
1H), 2.40-2.47 (m, 2H), 1.75 (m, 1H), 2.21 (s, 3H), 1.39 (s, 9H).
Embodiment 8:(3R, 5S) -6- acetoxy-3,5- dihydroxy hecanoic acid t-butyl ester (III) preparation
In 500mL three-neck flask, 100mL tetrahydrofuran is added, after mixed liquor is cooled to -20~-10 DEG C, is added
13.3g chiral oxazaborolidine (1.3eq) and 10.0g chemical compounds I.After stirring and evenly mixing, 30mL borine is slowly added dropwise into reaction solution
Tetrahydrofuran solution.After being added dropwise, reaction mixture is stirred overnight rear TLC monitoring end of reaction.Reaction solution is slowly added dropwise
The quenching reaction into 50mL saturated ammonium chloride solution, after being added dropwise, quenching reaction liquid is warming up to 30~40 DEG C and stirs 1 hour.
3 × 200mL ethyl acetate is added into the reaction mixture after being quenched and extracts product.Merge and extracts organic phase three times, 35~45
DEG C yellow slurry 8.49g, yield 83.6% is concentrated under reduced pressure to obtain.
Embodiment 9:(3R, 5S) -6- acetoxy-3,5- dihydroxy hecanoic acid t-butyl ester (III) preparation
In 500mL three-neck flask, 100mL tetrahydrofuran and 20mL methanol is added, mixed liquor is cooled to -15~-5 DEG C
Afterwards, diethylmethoxyborane 50mL, 10.0g chemical compounds I, 3.68g sodium borohydride (2.5eq), reaction mixture stirring is added
TLC monitors end of reaction after overnight.50mL water quenching reaction is added dropwise into reaction solution, after being added dropwise, the heating of quenching reaction liquid
It is stirred 0.5 hour to 30~40 DEG C.3 × 200mL ethyl acetate is added into the reaction mixture after being quenched and extracts product.Merge
Organic phase is extracted three times, and 35~45 DEG C are concentrated under reduced pressure to obtain deep yellow color liquid.The deep yellow color liquid is separated through silica gel column chromatography, dichloro
Methane-methanol elution, obtains yellow liquid 5.1g, yield 50.3%.
Embodiment 10:
In 500mL three-necked bottle, III compound of 10.0g formula, 50mL toluene are sequentially added, stirring and dissolving adds 3.8g 2,
2- dimethoxy propane and 1.1g methanesulfonic acid are stirred at room temperature 8 hours.Saturated sodium bicarbonate solution is instilled into reaction solution, is adjusted
Water phase pH to 7~8.Organic layer is separated, 40~50 DEG C are concentrated under reduced pressure to obtain slurry.The addition 80mL hexane into slurry, 40~
50 DEG C of stirring dissolved clarifications, then it is cooled to 0~10 DEG C, a large amount of white solids are precipitated.Filtering, the washing of cold hexane solution, 35~45 DEG C subtract
Press dry dry 11.1g AST-8, yield 95.8%.ESI-MS:m/z 303.18 [M+H]+；1H-NMR(CD3Cl, 400MHz): δ
4.20-4.26(m,1H),3.92-3.97(m,1H),3.50-3.56(m,1H),3.41-3.47(m,1H),2.41-2.44(dd,
J=12.8,6.0Hz, 1H), 2.35 (d, J=7.2Hz, 1H), 2.23-2.28 (dd, J=12.8,6.0Hz, 1H), 1.13-
1.46(m,17H)。
Embodiment 11:
In 500mL three-necked bottle, 10g D-5,100mL methanol and 4.0g potassium carbonate are sequentially added, after being stirred to react 3 hours,
Filtering, filtrate are concentrated to dryness in 35~45 DEG C.150mL methylene chloride dissolved clarification is added in gained slurry, sequentially adds 3.0g
Sodium bicarbonate, 0.5g potassium bromide and 0.4gTEMPO.After mixture stirring is cooled to -5~5 DEG C, start to be added dropwise 50.0g 8% time
Sodium chlorate solution.It is stirred 1 hour for -5~5 DEG C after being added dropwise.TLC monitor end of reaction, be added 0.7g sodium thiosulfate and
10.0g water quenching reaction.Static layering, water layer are mentioned with 100mL methylene chloride is counter.Merge organic layer, 2 × 200mL of organic layer
Water washing.35~45 DEG C of organic layer after washing are dried under reduced pressure to obtain light red solid 8.2g D-7, yield 96.1%.ESI-MS:
m/z 281.14[M+Na]+；1H-NMR (DMSO-d6,400MHz): δ 9.49 (m, 1H), 4.50-4.52 (m, 1H), 4.26-4.33
(m, 1H), 2.41-2.51 (m, 1H), 2.22-2.28 (m, 1H), 1.74-1.78 (m, 2H), 1.31-1.39 (m, 15H).
Method of the invention is described by preferred embodiment, pertinent art obviously can in the content of present invention and
In range to heretofore described methods and applications it is necessary to the slightly appropriate common-sense in place adjustment, change and group
It closes, carrys out implementation and application the technology of the present invention.Those skilled in the art can also use for reference the content of present invention, by being suitably modified technological parameter
It realizes.In particular, it should be pointed out that it is all be similarly modified and adjust it is apparent to those skilled in the art, all
It should be deemed to be included within the present invention.
Claims (9)
1. a kind of intermediate of rosuvastain calcium, which is characterized in that structure is as shown in formula I:
。
2. a kind of method for preparing type I compound, which comprises the steps of:
II compound of step A. formula is reacted with metal M, forms organometallic reagent；
Organometallic reagent obtained by step B.A step and CH3COOCH2COCl reacts to obtain type I compound.
Wherein,
X independently is halogen atom, is selected from Cl, Br, I, preferably Br；
M is metal, preferably magnesium and zinc.
3. method as described in claim 2, which is characterized in that the reaction in step A is preferably in the ether solvent of reflux
It carries out, including but not limited to ether, tetrahydrofuran, 2- methyltetrahydrofuran.
4. method as described in claim 2, which is characterized in that the molar ratio of II compound of formula and metal M be 1:1~
1:1.5, preferably 1:1.2~1:1.3.
5. method as described in claim 2, which is characterized in that II compound of formula and reagent C H3COOCH2Feeding intake for COCl rubs
You are than being 1:1~1:5, preferably 1:2~1:3.
6. a kind of application of type I compound as described in claim 1, which is characterized in that the type I compound is used for formula
The synthesis of III compound.
。
7. a kind of application of type I compound as described in claim 1 in the calcium of synthesizing rosuvastatin spit of fland.
8. application as described in claim 7, which is characterized in that can be used of conversion of type I compound to III compound of formula
It learns reduction method to realize, the realization of enzyme process restoring method can also be used.
9. the application as described in claim 6 and 8, which is characterized in that reducing agent used in reduction method process is selected from boron hydrogen
Compound, chiral borane derivative, aluminium isopropoxide, dicarbapentaborane reductase, preferably dicarbapentaborane reductase.
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