CN106496182A - A kind of preparation method of atorvastatin surveyor's chain intermediate - Google Patents
A kind of preparation method of atorvastatin surveyor's chain intermediate Download PDFInfo
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Abstract
The invention belongs to technical field of organic chemistry, specially a kind of atorvastatin surveyor's chain intermediate 2 ((4R,6S) 6 (2 (benzyloxy) ethyl) 2,2 dimethyl, 1,3 dioxane, 4 base) ethamine（I）Preparation method.The inventive method will obtained in D aspartic acids (R) 1 benzyloxy oneself 5 alkene, 3 alcohol（II）Through t-butoxycarbonylating, the cyclisation of intramolecular bromo, acetonylidene protection, acetylation, hydrolysis, aldehyde obtained in oxidation, then target compound 2 ((4 is obtained with nitromethane through steps such as Henry reactions, acetylation, reductionR,6S) 6 (2 (benzyloxy) ethyl) 2,2 dimethyl, 1,3 dioxane, 4 base) ethamine（I）.Raw material of the present invention is easy to get, and each step reaction condition is gentle, easy to operate, is easy to industrialized production.
Description
Technical field
The invention belongs to technical field of organic chemistry, and in particular to a kind of atorvastatin surveyor's chain intermediate -- 2- ((4R,
6S) -6- (2- (benzyloxy) ethyl) -2,2- dimethyl -1,3- dioxane -4- bases) ethamine（I）Preparation method.
Background technology
2-((4R,6S) -6- (2- (benzyloxy) ethyl) -2,2- dimethyl -1,3- dioxane -4- bases) ethamine（I）It is
The important intermediate of synthesis hypolipidemic Atorvastatin calcium.Its structure is as follows：
2010, M E. Maier etc.（Tetrahedron, 2010, 66:9738-9744）Reported first compound（I）'s
Synthetic method, its synthetic route are as follows：
Complex catalysis aldehyde radical asymmetric allyation of the method twice using chiral phosphorus ligand with metal iridium extends side chain simultaneously
Stereocenter is built, the used chiral phosphorus ligand of the route is sufficiently expensive with iridium price, and is difficult to reclaim, and does not possess work completely
Industry using value.
2012, M E. Maier etc.（Eur. J. Org. Chem., 2012, (13):6576-6585）Report again
Another compound（I）Synthetic route, as follows：
Tryptophan used in the route-boron derivative chiral catalyst is prepared difficult, it is impossible to reclaim, is limited without commercial source
The commercial Application of the route is made.
Therefore, said method is not suitable for commercial production.
Content of the invention
It is an object of the invention to provide a kind of low cost, prepare simple, reclaim in the middle of convenient atorvastatin surveyor's chain
Body 2- ((4R,6S) -6- (2- (benzyloxy) ethyl) -2,2- dimethyl -1,3- dioxane -4- bases) ethamine（I）Preparation side
Method.
The atorvastatin surveyor's chain intermediate 2- ((4 that the present invention is providedR,6S) -6- (2- (benzyloxy) ethyl) -2,2- two
Six ring -4- bases of methyl-1,3-dioxy) ethamine（I）Preparation method, its synthetic route is as follows：
Comprise the following steps that：
（1）Compound（II）React under zinc acetate catalysis in organic solvent with Bis(tert-butoxycarbonyl)oxide, compound is obtained
（III）, reaction temperature is 0 ~ 150 DEG C, and the response time is 2 ~ 48h；
（2）Compound（III）In the presence of an inorganic base with brominated reagent through bromo cyclization, preparedization in organic solvent
Compound（IV）, reaction temperature is -80 ~ 0 DEG C, and the response time is 0.5 ~ 6h；
（3）Compound（IV）React with acetone in the presence of acid, compound is obtained（V）, reaction temperature is -20 ~ 35 DEG C, reaction
Time is 2 ~ 48h；
（4）Compound（V）In organic solvent and alkali-metal acetic acid reactant salt, compound is obtained（VI）, reaction temperature be 50 ~
200 DEG C, the response time is 2 ~ 48h；
（5）Compound（VI）Hydrolyzed in organic solvent in the presence of base, compound is obtained（VII）, reaction temperature is -20-
35 DEG C, the response time is 0.1 ~ 12h；
（6）Compound（VII）In the mixed solvent of organic solvent, water and buffer salt composition, in tetramethyl piperidine nitrogen oxides
（TEMPO）Under catalysis, oxidized dose of oxidation is obtained compound（VIII）, reaction temperature be -5-10 DEG C, the response time be 0.1 ~
6h；
（7）Compound（VIII）In organic solvent and in the presence of potassium fluoride, react through Henry with nitromethane, chemical combination is obtained
Thing（IX）, reaction temperature is 0 ~ 50 DEG C, and the response time is 1 ~ 24h；
（8）Compound（IX）In organic solvent and in the presence of alkali, acylation reaction is carried out with acetylation reagent, compound is obtained
（X）, reaction temperature is -20 ~ 35 DEG C, and the response time is 0.5 ~ 24h；
（9）Compound（X）In organic solvent through borohydride reduction, compound is obtained（XI）, reaction temperature is -20 ~ 35 DEG C,
Response time is 0.5 ~ 12h；
（10）Compound（XI）Through catalysis reduction in the presence of organic solvent and hydrogenation catalyst, compound is obtained（I）, reaction temperature
Spend for -0 ~ 50 DEG C, the response time is 0.5-12h.
In the present invention, initiation material（II）Can be according to document（B. J. Naysmith, M. A. Brimble. Org.
Lett., 2013, 15:2006–2009）It is obtained with the D-Asp that business is easy to get as raw material is convenient.
In the present invention, by compound（II）Prepare compound（III）When, the organic solvent for being used is that C1-C4 is monosubstituted
Or polysubstituted halogenated hydrocarbons, C1-C4Monosubstituted or polysubstituted aromatic hydrocarbons, ethyl acetate, or the mixed solvent constituted by above-mentioned solvent, this
A little solvent sources are extensively, cheap.
In the present invention, by compound（III）Prepare compound（IV）When, the organic solvent for being used is that C1-C4 is monosubstituted
Or polysubstituted halogenated hydrocarbons, symmetrically or non-symmetrically C1-C4 alkyl ethers or cyclic ethers, acetonitrile.The inorganic base for being used is alkali-metal hydrogen
Oxide, carbonate or bicarbonate.The brominated reagent for being used is bromine, N-bromosuccinimide, DBDMH.
In the present invention, by compound（IV）Prepare compound（V）When, the acid for being used be sulphuric acid, Loprazolam, to methyl
One kind in benzenesulfonic acid, camphorsulfonic acid.
In the present invention, by compound（V）Prepare compound（VI）When, the organic solvent for being used is polar non-solute
Such as N,N-dimethylformamide, dimethyl sulfoxide, N-Methyl pyrrolidone.The acetate for being used be alkali-metal acetate or
C1-C4Acetate of the alkyl for amine.
In the present invention, by compound（VI）Prepare compound（VII）When, the organic solvent for being used is C1-C4Alcohol.Institute
The alkali for using is alkali-metal hydroxide, C1-C4Alkoxide, carbonate.
In the present invention, by compound（VII）Prepare compound（VIII）When, the organic solvent for being used is taken for C1-C4 is mono-
Generation or polysubstituted halogenated hydrocarbons.Buffer salt is alkali-metal acetate, bicarbonate, hydrophosphate, dihydric phosphate or above-mentioned salt
The mixing buffer salt system for being constituted.The oxidant for being used is sym-closene or sodium hypochlorite.
In the present invention, by compound（VIII）Prepare compound（IX）When, the organic solvent for being used is C1-C4Alcohol.
In the present invention, by compound（IX）Prepare compound（X）When, the organic solvent for being used be C1-C4 monosubstituted or
Polysubstituted halogenated hydrocarbons, symmetrically or non-symmetrically C1-C4 alkyl ethers or cyclic ethers, ethyl acetate, C1-C4Monosubstituted or polysubstituted aromatic hydrocarbons.Institute
The alkali for using is triethylamine, pyridine or DMAP.The acetylation reagent for being used is acetic anhydride or chloroacetic chloride.
In the present invention, by compound（X）Prepare compound（XI）When, the organic solvent for being used is C1-C4Alcohol.Made
Boron hydride is alkali-metal boron hydride.
In the present invention, by compound（XI）Prepare compound（I）When, the organic solvent for being used is C1-C4Alcohol, acetic acid
Ethyl ester, acetic acid.The hydrogenation catalyst for being used is 5 ~ 20% palladium charcoals, 5 ~ 20% palladium dydroxide charcoals, Raney nickel.
The present invention optimum condition be：
（1）By compound（II）Prepare compound（III）When, organic solvent is preferably as dichloromethane or toluene.Reaction temperature
20 ~ 50 DEG C and 6 ~ 24h are preferably with the time；
（2）By compound（III）Prepare compound（IV）When, organic solvent is preferably dichloromethane, acetonitrile, tetrahydrofuran.Institute
The inorganic base for using is preferably sodium carbonate or potassium carbonate.The brominated reagent for being used is preferably bromine.Reaction temperature and time are excellent
Elect -40 ~ -20 DEG C and 1 ~ 3h as；
（3）By compound（IV）Prepare compound（V）When, the acid for being used is preferably p-methyl benzenesulfonic acid.Reaction temperature and when
Between be preferably 0 ~ 25 DEG C and 6 ~ 12h；
（4）By compound（V）Prepare compound（VI）When, organic solvent is preferably DMF.The vinegar for being used
Hydrochlorate is preferably sodium acetate or potassium acetate.Reaction temperature and time are preferably 100 ~ 150 DEG C and 6 ~ 12h；
（5）By compound（VI）Prepare compound（VII）When, organic solvent is preferably methanol.The alkali for being used is sodium hydroxide
Or Feldalat NM.Reaction temperature and time are preferably 0 ~ 25 DEG C and 0.5 ~ 2h；
（6）By compound（VII）Prepare compound（VIII）When, organic solvent is preferably dichloromethane.Buffer salt is preferably carbon
Sour hydrogen sodium.The oxidant for being used is preferably sym-closene.Reaction temperature and time are preferably 0 ~ 5 DEG C and 0.5 ~ 1h；
（7）By compound（VIII）Prepare compound（IX）When, organic solvent is preferably isopropanol.Reaction temperature and time are preferred
For 20 ~ 35 DEG C and 3 ~ 6h；
（8）By compound（IX）Prepare compound（X）When, organic solvent is preferably dichloromethane, ethyl acetate.Alkali is preferably 4-
Dimethylamino naphthyridine.Acetylation reagent is acetic anhydride.Reaction temperature and time are preferably 0 ~ 25 DEG C and 1 ~ 3h；
（9）By compound（X）Prepare compound（XI）When, organic solvent is preferably methanol or ethanol.Boron hydride is preferably boron
Sodium hydride.Reaction temperature and time are preferably 0 ~ 25 DEG C and 1 ~ 3h；
（10）By compound（XI）Prepare compound（I）When, organic solvent is preferably methanol.Hydrogenation catalyst is 5 ~ 10% palladium charcoals.
Reaction temperature and time are preferably 20 ~ 35 DEG C and 6 ~ 12h.
The invention has the advantages that raw material is easy to get, reaction condition is gentle, the features such as easy to operate, is suitable for industrialized production.
Specific embodiment
Following examples are better described present invention.But the invention is not restricted to following embodiments.
Embodiment 1, the tert-butyl group (R) -1- benzyloxy hex- 5- alkene -3- base carbonic esters（III）Preparation
Will (R) -1- benzyloxy hex- 5- enols（II）（100g, 485mmol）, dichloromethane（500mL）, zinc acetate（9g,
4.9mmol）And Bis(tert-butoxycarbonyl)oxide（127g, 582mmol）Put in reaction bulb, heated and stirred backflow 12h, reaction finish, cooling
To room temperature, filter, after filtrate concentrated solvent, pale yellow oily liquid is obtained through vacuum distillation（III）（134g, 91%）.
Embodiment 2, the tert-butyl group (R) -1- benzyloxy hex- 5- alkene -3- base carbonic esters（III）Preparation
Will (R) -1- benzyloxy hex- 5- enols（200g, 0.97mol）, toluene（1L）, zinc acetate（18g, 9.8mmol）With two carbon
Sour di tert butyl carbonate（233g, 1.07mol）Put in reaction bulb, in 80 DEG C of heated and stirred 6h, reaction is finished, and is cooled to room temperature, filters, filter
Pale yellow oily liquid is obtained through vacuum distillation after liquid concentrated solvent（III）（279g, 94%）.
Embodiment 3, (4S,6S) -4- (2- benzyloxyethyls) -6- bromomethyl -2- oxo -1,3- dioxane（IV）System
Standby
By compound（III）（50g, 163mmol）, potassium carbonate（34g, 244mmol）And dichloromethane（500mL）Put dry reaction
In bottle, Deca bromine under -40 DEG C with stirring（31g, 196mmol）.Drip in 0.5h and finish, insulated and stirred 1h, reaction finish, and use 5%
Sodium sulfite solution is quenched, and which floor layering, water mutually with dichloromethane extraction, be associated with, and washes, anhydrous sodium sulfate drying, mistake
Filter, filtrate are concentrated to give colourless oil liquid（IV）（52.6g, 98%）.
Embodiment 4, (4S,6S) -4- (2- benzyloxyethyls) -6- bromomethyl -2- oxo -1,3- dioxane（IV）System
Standby
By compound（III）（50g, 163mmol）, potassium carbonate（34g, 244mmol）And acetonitrile（500mL）Put dry reaction bottle
In, Deca bromine under -30 DEG C with stirring（31g, 196mmol）.Drip in 0.5h and finish, insulated and stirred 3h, reaction finish, sub- with 5%
Sodium bisulfate is quenched, and which floor layering, water mutually with dichloromethane extraction, be associated with, and washes, anhydrous sodium sulfate drying, filters,
Filtrate is concentrated to give colourless oil liquid（IV）（51.2g, 95%）.
Embodiment 5, (4S,6S) -4- (2- benzyloxyethyls) -6- bromomethyl -2,2- dimethyl -1,3- dioxane（V）'s
Prepare
By compound（IV）（70g, 213mmol）, p-methyl benzenesulfonic acid（20g, 106mmol）And acetone（500mL）Put in reaction bulb,
12h is stirred in 25 DEG C.Reaction is finished, and is adjusted to pH6 ~ 7 with saturated sodium bicarbonate solution, with dichloromethane extraction, merges organic layer, water
Wash, anhydrous sodium sulfate drying, filter, residue vacuum distillation after filtrate concentration obtains colourless oil liquid（V）（42.3g, 58%）.
Embodiment 6, (4S,6S) -4- (2- benzyloxyethyls) -6- bromomethyl -2,2- dimethyl -1,3- dioxane（V）'s
Prepare
By compound（IV）（33g, 100mmol）, Loprazolam（9.6g, 100mmol）And acetone（200mL）Put in reaction bulb,
36h is stirred in 0 DEG C.Reaction is finished, and is adjusted to pH6 ~ 7 with saturated sodium bicarbonate solution, with dichloromethane extraction, merges organic layer, water
Wash, anhydrous sodium sulfate drying, filter, residue vacuum distillation after filtrate concentration obtains colourless oil liquid（V）（21.7g, 63%）.
Embodiment 7, ((4S,6S) -6- (2- benzyloxyethyls) -2,2- dimethyl -1,3- dioxane -4- bases) methyl acetic acid
Ester（VI）Preparation
By compound（V）（50g, 146mmol）, sodium acetate（35.8g, 437mmol）WithN,N- dimethylformamide（250mL）Put
In reaction bulb, 8h is stirred in 150 DEG C.Reaction is finished, and is cooled to room temperature, adds water（250mL）, with dichloromethane extraction, it is associated with
Machine layer, washing, anhydrous sodium sulfate drying are filtered, residue vacuum distillation after filtrate concentration, obtain colourless oil liquid（VI）
（37.6g, 80%）.
Embodiment 8, ((4S,6S) -6- (2- benzyloxyethyls) -2,2- dimethyl -1,3- dioxane -4- bases) methyl acetic acid
Ester（VI）Preparation
By compound（V）（50g, 146mmol）, potassium acetate（43g, 438mmol）And dimethyl sulfoxide（250mL）Put reaction bulb
In, 4h is stirred in 180 DEG C.Reaction is finished, and is cooled to room temperature, adds water（250mL）, with dichloromethane extraction, merge organic layer, water
Wash, anhydrous sodium sulfate drying, filter, residue vacuum distillation after filtrate concentration obtains colourless oil liquid（VI）（34.7g,
74%）.
Embodiment 9, ((4S,6S) -6- (2- benzyloxyethyls) -2,2- dimethyl -1,3- dioxane -4- bases) methanol
（VII）Preparation
By compound（VI）（50g, 155mmol）, potassium carbonate（10.7g, 78mmol）And methanol（250mL）Put in reaction bulb, in
25 DEG C of stirring 2h.Reaction is finished, and filters, and filtrate is concentrated to dryness, and adds water（250mL）, extracted with dichloromethane, merge organic layer,
Washing, anhydrous sodium sulfate drying are filtered, and filtrate concentrates, and obtains colourless oil liquid（VII）（39.1g, 90%）.
Embodiment 10, ((4S,6S) -6- (2- benzyloxyethyls) -2,2- dimethyl -1,3- dioxane -4- bases) formaldehyde
（VIII）Preparation
By compound（VII）（80g, 285mmol）, sodium bicarbonate（144g, 1.7mol）, tetramethyl piperidine nitrogen oxides
（0.45g, 3mmol）, dichloromethane（400mL）And water（400mL）Put in reaction bulb, in 0 DEG C and under stirring, control temperature is not high
In 5 DEG C, sym-closene is dividedly in some parts（33.2g, 143mmol）.Finish, insulated and stirred 0.5h.Reaction is finished, and separates organic
Layer, water layer are extracted with dichloromethane, merge organic layer, and washing, anhydrous sodium sulfate drying are filtered, vacuum distillation after filtrate concentration,
Obtain colourless oil liquid（VII）（60g, 76%）.
Embodiment 11, ((4S,6S) -6- (2- benzyloxyethyls) -2,2- dimethyl -1,3- dioxane -4- bases) formaldehyde
（VIII）Preparation
By compound（VII）（40g, 143mmol）, sodium bicarbonate（120g, 1.43mol）, tetramethyl piperidine nitrogen oxides
（0.23g, 1.5mmol）, dichloromethane（400mL）And water（400mL）Put in reaction bulb, in 0 DEG C and under stirring, control temperature is not
It is higher than 5 DEG C, the liquor natrii hypochloritises of 6% effective chlorine of Deca（100mL）.Drop finishes, insulated and stirred 0.5h.Reaction is finished, and separates organic
Layer, water layer are extracted with dichloromethane, merge organic layer, successively with saturation sulfurous acid solution and water washing, anhydrous sodium sulfate drying,
Filter, vacuum distillation after filtrate concentration obtains colourless oil liquid（VIII）（27.4g, 69%）.
Embodiment 12,1- ((4S,6S) -6- (2- benzyloxyethyls) -2,2- dimethyl -1,3- dioxane -4- bases) -2-
Nitroethyl alcohol（IX）Preparation
By compound（VIII）（80g, 287mmol）, potassium fluoride（1.8g, 30mmol）And isopropanol（800mL）Put in reaction bulb,
Deca nitromethane under 25 DEG C with stirring（43.8g, 717mmol）.Drop finishes, and continues stirring 4h.Reaction is finished, and filters, and filtrate is dense
It is reduced to dry, obtains colourless oil liquid（IX）（92.7g, 95%）.
Embodiment 13, acetic acid 1- ((4S,6S) -6- (2- benzyloxyethyls) -2,2- dimethyl -1,3- dioxane -4- bases) -
2- nitro ethyl esters（X）Preparation
By compound（IX）（100g, 295mmol）, DMAP（0.7g, 6mmol）And dichloromethane（500mL）Put
In reaction bulb, Deca acetic anhydride under 25 DEG C with stirring（36g, 353mmol）.Drop finishes, and continues stirring 2h.Reaction is finished, and adds water
（250mL）, organic layer is separated, water layer dichloromethane extraction merges organic layer, and washing, anhydrous sodium sulfate drying are filtered, filter
Liquid is concentrated to dryness, and obtains colourless oil liquid（X）（106.7g, 95%）.
Embodiment 14, acetic acid 1- ((4S,6S) -6- (2- benzyloxyethyls) -2,2- dimethyl -1,3- dioxane -4- bases) -
2- nitro ethyl esters（X）Preparation
By compound（IX）（100g, 295mmol）, triethylamine（32.8g, 325mmol）And ethyl acetate（500mL）Put reaction bulb
In, Deca chloroacetic chloride under 25 DEG C with stirring（25.5g, 325mmol）.Drop finishes, and continues stirring 1h.Reaction is finished, and adds water
（250mL）, organic layer is separated, aqueous layer with ethyl acetate is extracted, and merges organic layer, and washing, anhydrous sodium sulfate drying are filtered, filter
Liquid is concentrated to dryness, and obtains colourless oil liquid（X）（103.5g, 92%）.
Embodiment 15, (4S,6R) -4- (2- benzyloxyethyls) -2,2- dimethyl -6- (2- nitro-ethyls) -1,3- dioxies six
Ring（XI）Preparation
By sodium borohydride（11.9g, 314mmol）And ethanol（300mL）Put in reaction bulb, compound is slowly added dropwise in 0 ~ 5 DEG C（X）
（30g, 78mmol）.Drop finishes, and is warmed to room temperature stirring 2h.Reaction is finished, and is adjusted to pH6 ~ 7, after concentration ethanol, raffinate with 5% hydrochloric acid
With dichloromethane extraction, merge organic layer, washing, anhydrous sodium sulfate drying are filtered, vacuum distillation after filtrate concentration is obtained colourless
Oily liquids（XI）（20.3g, 80%）.
Embodiment 16,2- ((4R,6S) -6- (2- benzyloxyethyls) -2,2- dimethyl -- 1,3- dioxane -4- bases) second
Amine（I）Preparation
By compound（XI）（50g, 155mmol）, 10% palladium charcoal（1g）Put in reaction bulb with methanol, in atmosphere of hydrogen lower 25 DEG C often
Pressure hydrogenation 8h.Reaction is finished, and filters, vacuum distillation after filtrate concentration, obtains colourless oil liquid（I）（36.3g, 80%）.
Claims (21)
1. a kind of 2- ((4R,6S) -6- (2- (benzyloxy) ethyl) -2,2- dimethyl -1,3- dioxane -4- bases) ethamine（I）
Preparation method, it is characterised in that synthetic route is as follows：
Concretely comprise the following steps：
（1）Compound（II）React under zinc acetate catalysis in organic solvent with Bis(tert-butoxycarbonyl)oxide, compound is obtained
（III）, reaction temperature is 0 ~ 150 DEG C, and the response time is 2 ~ 48h；
（2）Compound（III）In the presence of an inorganic base with brominated reagent through bromo cyclization, preparedization in organic solvent
Compound（IV）, reaction temperature is -80 ~ 0 DEG C, and the response time is 0.5 ~ 6h；
（3）Compound（IV）React with acetone in the presence of acid, compound is obtained（V）, reaction temperature is -20 ~ 35 DEG C, reaction
Time is 2 ~ 48h；
（4）Compound（V）In organic solvent and alkali-metal acetic acid reactant salt, compound is obtained（VI）, reaction temperature be 50 ~
200 DEG C, the response time is 2 ~ 48h；
（5）Compound（VI）Hydrolyzed in organic solvent in the presence of base, compound is obtained（VII）, reaction temperature is -20-
35 DEG C, the response time is 0.1 ~ 12h；
（6）Compound（VII）In the mixed solvent of organic solvent, water and buffer salt composition, in tetramethyl piperidine nitrogen oxides
（TEMPO）Under catalysis, oxidized dose of oxidation is obtained compound（VIII）, reaction temperature be -5-10 DEG C, the response time be 0.1 ~
6h；
（7）Compound（VIII）In organic solvent and in the presence of potassium fluoride, react through Henry with nitromethane, chemical combination is obtained
Thing（IX）, reaction temperature is 0 ~ 50 DEG C, and the response time is 1 ~ 24h；
（8）Compound（IX）In organic solvent and in the presence of alkali, acylation reaction is carried out with acetylation reagent, compound is obtained
（X）, reaction temperature is -20 ~ 35 DEG C, and the response time is 0.5 ~ 24h；
（9）Compound（X）In organic solvent through borohydride reduction, compound is obtained（XI）, reaction temperature is -20 ~ 35 DEG C,
Response time is 0.5 ~ 12h；
（10）Compound（XI）Through catalysis reduction in the presence of organic solvent and hydrogenation catalyst, compound is obtained（I）, reaction temperature
Spend for -0 ~ 50 DEG C, the response time is 0.5-12h.
2. preparation method as claimed in claim 1, it is characterised in that step（1）Used in organic solvent selected from C1-C4 mono-
Replace or polysubstituted halogenated hydrocarbons, C1-C4Monosubstituted or polysubstituted aromatic hydrocarbons, ethyl acetate, or the mixing constituted by above-mentioned solvent is molten
Agent.
3. preparation method as claimed in claim 1 or 2, it is characterised in that step（2）Used in organic solvent be selected from C1-
C4 is monosubstituted or polysubstituted halogenated hydrocarbons, symmetrically or non-symmetrically C1-C4 alkyl ethers or cyclic ethers, acetonitrile；The inorganic base for being used is alkali
The hydroxide of metal, carbonate or bicarbonate；The brominated reagent for being used is bromine, N-bromosuccinimide or dibromo
Glycolylurea.
4. preparation method as claimed in claim 3, it is characterised in that step（3）Used in acid be sulphuric acid, methane sulphur
Acid, p-methyl benzenesulfonic acid, the one kind in camphorsulfonic acid.
5. the preparation method as described in claim 1,2 or 4, it is characterised in that step（4）Used in organic solvent be polarity
Aprotic solvent, selected from DMF, dimethyl sulfoxide, N-Methyl pyrrolidone；The acetate for using is selected from alkali
The acetate or C of metal1-C4Acetate of the alkyl for amine.
6. preparation method as claimed in claim 5, it is characterised in that step（5）Used in organic solvent be selected from C1-C4's
Alcohol；The alkali for using is selected from alkali-metal hydroxide, C1-C4Alkoxide or carbonate.
7. the preparation method as described in claim 1,2,4 or 6, it is characterised in that step（6）Used in organic solvent be selected from
C1-C4 is monosubstituted or polysubstituted halogenated hydrocarbons；Buffer salt is selected from alkali-metal acetate, bicarbonate, hydrophosphate, biphosphate
The mixing buffer salt system constituted by salt or above-mentioned salt；The oxidant for using is sym-closene or sodium hypochlorite.
8. preparation method as claimed in claim 7, it is characterised in that step（7）Used in organic solvent be selected from C1-C4's
Alcohol.
9. the preparation method as described in claim 1,2,4,6 or 8, it is characterised in that step（8）Used in organic solvent choosing
From C1-C4 is monosubstituted or polysubstituted halogenated hydrocarbons, symmetrically or non-symmetrically C1-C4 alkyl ethers or cyclic ethers, ethyl acetate, C1-C4Monosubstituted
Or polysubstituted aromatic hydrocarbons；The alkali for being used is selected from triethylamine, pyridine or DMAP；The acetylation reagent for being used is vinegar
Acid anhydride or chloroacetic chloride.
10. preparation method as claimed in claim 9, it is characterised in that step（9）Used in organic solvent be selected from C1-C4's
Alcohol；The boron hydride for being used is alkali-metal boron hydride.
11. preparation methoies as described in claim 1,2,4,6,8 or 10, it is characterised in that step（10）Used in organic
Solvent is selected from C1-C4Alcohol, ethyl acetate, acetic acid；The hydrogenation catalyst for being used is 5 ~ 20% palladium charcoals, 5 ~ 20% palladium dydroxide charcoals
Or Raney nickel.
12. preparation methoies as described in claim 1 or 11, it is characterised in that step（1）Used in the excellent of organic solvent be
Dichloromethane or toluene, reaction temperature are 20 ~ 50 DEG C, and the response time is 6 ~ 24h.
13. preparation methoies as described in claim 1 or 11, it is characterised in that step（2）Used in organic solvent be dichloromethane
Alkane, acetonitrile or tetrahydrofuran；The inorganic base for using is sodium carbonate or potassium carbonate；The brominated reagent for being used is bromine；Reaction temperature
Spend for -40 ~ -20 DEG C, the response time is 1 ~ 3h.
14. preparation methoies as described in claim 1 or 11, it is characterised in that step（3）Used in acid be to methylbenzene sulphur
Acid；Reaction temperature is 0 ~ 25 DEG C, and reflecting time is 6 ~ 12h.
15. preparation methoies as described in claim 1 or 11, it is characterised in that step（4）Used in organic solvent be N, N-
Dimethylformamide, the acetate for using are sodium acetate or potassium acetate, and reaction temperature is 100 ~ 150 DEG C, the response time is 6 ~
12h.
16. preparation methoies as described in claim 1 or 11, it is characterised in that step（5）Used in organic solvent be first
Alcohol, the alkali for using are sodium hydroxide or Feldalat NM, and reaction temperature is 0 ~ 25 DEG C, and the response time is 0.5 ~ 2h.
17. preparation methoies as described in claim 1 or 11, it is characterised in that step（6）Used in organic solvent be dichloro
Methane, buffer salt are sodium bicarbonate, and the oxidant for using is sym-closene；Reaction temperature is 0 ~ 5 DEG C, and the response time is
0.5~1h.
18. preparation methoies as described in claim 1 or 11, it is characterised in that step（7）Used in electric organic solvent be isopropyl
Alcohol, reaction temperature are 20 ~ 35 DEG C, and the response time is 3 ~ 6h.
19. preparation methoies as described in claim 1 or 11, it is characterised in that step（8）Used in organic solvent be dichloro
Methane or ethyl acetate, alkali are DMAP, and acetylation reagent is acetic anhydride；Reaction temperature is 0 ~ 25 DEG C, the response time
For 1 ~ 3h.
20. preparation methoies as described in claim 1 or 11, it is characterised in that step（9）Used in organic solvent be methanol
Or ethanol, boron hydride is sodium borohydride；Reaction temperature is 0 ~ 25 DEG C, and the response time is 1 ~ 3h.
21. preparation methoies as described in claim 1 or 11, it is characterised in that step（10）Used in organic solvent be first
Alcohol, hydrogenation catalyst are 5 ~ 10% palladium charcoals；Reaction temperature is 20 ~ 35 DEG C, and the response time is 6 ~ 12h.
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| CN109836341A (en) * | 2017-11-28 | 2019-06-04 | 技源科技(中国)有限公司 | A kind of preparation method of salicylamine acetate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104356109A (en) * | 2014-11-12 | 2015-02-18 | 复旦大学 | Preparation method of 2-(( 4R,6S)-6-bromoethyl-2,2-dimethyl-1,3-dioxyhexacyclo-4-yl)acetate |
| WO2016122325A1 (en) * | 2015-01-30 | 2016-08-04 | Rijksuniversiteit Groningen | Methods for providing intermediates in the synthesis of atorvastatin. |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104356109A (en) * | 2014-11-12 | 2015-02-18 | 复旦大学 | Preparation method of 2-(( 4R,6S)-6-bromoethyl-2,2-dimethyl-1,3-dioxyhexacyclo-4-yl)acetate |
| WO2016122325A1 (en) * | 2015-01-30 | 2016-08-04 | Rijksuniversiteit Groningen | Methods for providing intermediates in the synthesis of atorvastatin. |
Non-Patent Citations (3)
| Title |
|---|
| PRAMOD SAWANT ET AL.: "A novel strategy towards the atorvastatin lactone", 《TETRAHEDRON》 * |
| PRAMOD SAWANT ET AL.: "Synthesis of Atorvastatin Lactone Linker Constructs for Target Fishing", 《EUR. J. ORG. CHEM》 * |
| 王继宇等: "阿托伐他汀的全合成研究进展", 《合成化学》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109836341A (en) * | 2017-11-28 | 2019-06-04 | 技源科技(中国)有限公司 | A kind of preparation method of salicylamine acetate |
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