CN108586427A - The preparation method of Atorvastatin calcium intermediate - Google Patents
The preparation method of Atorvastatin calcium intermediate Download PDFInfo
- Publication number
- CN108586427A CN108586427A CN201810653383.0A CN201810653383A CN108586427A CN 108586427 A CN108586427 A CN 108586427A CN 201810653383 A CN201810653383 A CN 201810653383A CN 108586427 A CN108586427 A CN 108586427A
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- solution
- reaction
- atorvastatin calcium
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to field of medicine and chemical technology, more particularly to pharmaceutical field, more particularly to the preparation method of Atorvastatin calcium intermediate, by the way that compound ii is first prepared into lithium reagent, it is reacted again with methylchloroformate, introduce ester group, it is ester group-aminated at amide, dehydration of amide, finally reduction cyano obtains preparation among target compound this completely new Atorvastatin calcium, synthesis compound VI can be prepared under the premise of without using extremely toxic substances such as hydrogen cyanide, hydrohalogenic acid salts, and utilizes VI prepare compound I of compound.Reagent safety employed in whole preparation process, environmental protection, is a kind of preparation method more suitable for industrialized production.
Description
Technical field
The invention belongs to field of medicine and chemical technology, more particularly to pharmaceutical field, and in particular to Atorvastatin calcium intermediate
Preparation method.
Background technology
Atorvastatin calcium（Atorvastatin Calcium）By Warner-Lambert（Now it is incorporated to Pfizer）Development is opened
Hair obtained FDA approvals in 1996 and is listed in the U.S., is mainly applicable to treatment hypercholesterolemia and mixed type hyperlipidemia
Disease.
(4R-Cis) -6- aminoethyl -2,2- dimethyl -1,3- dioxolanes-hecanoic acid t-butyl ester（125995-13-3）（Change
Close object I）It is crucial midbody compound in Atorvastatin calcium synthesis.
Currently, the synthesis route that the preparation method of chemical compounds I follows substantially is：
Therefore, the key intermediate compound that compound VI is synthesized as chemical compounds I, in the preparation work of Atorvastatin calcium
There is important research significance, synthetic method, synthesis technology are current Atorvastatin calcium study on the synthesis in skill R＆D process
In hot issue.
Currently, there are two main classes for the preparation method of compound VI, first kind method is using double hydroxyls after first cyano substitution
Protection, the second class method are cyano substitutions after first double hydroxyl protections.
It can be seen that although both preparation methods are different on yield and reaction condition, for example for method one
For, yield can reach 81%, and for method two, yield is only capable of reaching 11%, while temperature is reacted in method two
Degree requires 100 DEG C, and the reaction time even requires 30 hours.But both methods is there are one common ground in synthesis technology,
Two methods are required for using NaCN.And during synthesis, it is also necessary to use hydrogen cyanide equal solvent as reaction medium.
For those skilled in the art, hydrogen cyanide, hydrohalogenic acid salt etc. belong to extremely toxic substance.These substances are not only right
Human body is very harmful, and seriously pollutes environment.Using hydrogen cyanide, hydrohalogenic acid salt as reaction raw materials, current state is not met not only
The main trend of family's environmental protection, and also be difficult to buy.This just further increases the manufacturing cost of compound VI, to further increase
The manufacturing cost of Atorvastatin calcium is added.
Therefore, in the case that research and development are without using extremely toxic substances such as hydrogen cyanide, hydrohalogenic acid salts, how compound is prepared
VI has great importance.
Invention content
The technical problem to be solved by the present invention is under the premise of without using hydrogen cyanide, hydrohalogenic acid salt, provide a kind of new
The synthetic route of the preparation method of Atorvastatin calcium intermediate, this method is as follows：
。
It is further preferred that the preparation method can be specifically described as including the following steps：
The first step：Compound III is obtained by the reaction with synthesis in compound II；
Second step：Under cryogenic conditions, methylchloroformate is mixed with compound III, then increases temperature to room temperature, compound
Compound IV is obtained by the reaction with methylchloroformate in III；
Third walks：Under alkaline condition, compound V is obtained by the reaction in the methanol solution of compound IV and ammonia；
4th step：For compound V under the action of dehydrating agent, dehydration generates compound VI.
Preferably, above-mentioned first step reaction is in ether, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, dichloromethane, toluene, two
A kind of solution in toluene or optional two kinds and the two or more in the mixed solvents obtained according to the mixing of arbitrary mixed proportion into
Row reaction.
It is further preferred that above-mentioned first step reaction is reacted in ether or tetrahydrofuran solution.
When first step reaction dissolvent selects ether or tetrahydrofuran, reaction temperature is -5-10 DEG C.
Preferred technical solution is that the methylchloroformate is molten to methylchloroformate with the compound III modes mixed
Compound III is added dropwise in liquid.
Preferably, further include being quenched after the completion of second step reacts, extract, dry, concentration.
Further preferred technical solution is that the cryogenic conditions refer to -30 DEG C ~ 0 DEG C.
Wherein further preferred technical solution is that the solvent of methylchloroformate solution is ether, tetrahydrofuran, Isosorbide-5-Nitrae-
The mixing that one or more of dioxane, dichloromethane, toluene, dimethylbenzene are mixed to form according to arbitrary mixed proportion
Solvent.
The room temperature refers to 15 ~ 25 DEG C.
More preferably technical solution is that the cryogenic conditions refer to -20 DEG C.
And it is further preferred that the solvent of methylchloroformate solution is ether or tetrahydrofuran.
In a preferred technical solution, third step in be into the organic solution of compound IV be added ammonia methanol it is molten
Liquid is reacted.
Preferably, after the completion of three-step reaction, further include removing solvent, extract, dry, concentration.
The methanol solution of ammonia mentioned here can be the methanol that ammonia is dissolved in the saturated ammonia formed in methanol solution
Solution can also be the methanol solution that ammonium hydroxide is mixed to the ammonia obtained with methanol solution.
More preferably scheme is that the reaction temperature of three-step reaction is 15 ~ 100 DEG C.
Further preferred technical solution is that compound V is dissolved in organic solvent, in the effect of alkaline matter and dehydrating agent
Under, dehydration generates compound VI.
The wherein described organic solvent be preferably dichloromethane, 1,2- dichloroethanes, acetonitrile, n,N-Dimethylformamide,
The mixture of one or more of dimethyl sulfoxide (DMSO), benzene,toluene,xylene arbitrary proportion mixing.The wherein alkali
Property substance is preferably at least one of pyridine, 4-dimethylaminopyridine, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.
Wherein the dehydrating agent is that thionyl chloride, one kind in phosphorus oxychloride or thionyl chloride and phosphorus oxychloride are mixed according to arbitrary proportion
Close the mixture obtained.
Further, invention additionally discloses the methods of VI prepare compound I of compound is：Compound VI is dissolved in organic molten
Agent is reacted with hydrogen under the effect of the catalyst, obtains compound I.
It is further preferred that the reaction is described as, having for catalyst is added in the organic solvent solution of compound VI
The molten solution of machine carries out hydrogenation, after the completion of reaction, filters, and concentration is diluted with water, liquefied ammonia tune PH, is extracted, dry, concentration,
Obtain corresponding compound I.
Wherein preferred, the catalyst is palladium carbon, platinum carbon, one or two kinds of any of the above ratio of Raney's nickel
Mixture.The organic solvent is the alcohols such as methanol, ethyl alcohol, propyl alcohol, formic acid, acetic acid, propionic acid it is one or two kinds of more than
The mixture of arbitrary mixed proportion mixing.
In a preferred technical solution, catalyst is preferably palladium carbon or platinum carbon.
In another preferred technical solution, organic solvent is preferably acetic acid.
Further, invention additionally discloses preferred compound VI and hydrogen, under the effect of the catalyst, in 20-30 DEG C of item
It is reacted under part.
The present invention, which breaches, must use the plays such as hydrogen cyanide, hydrohalogenic acid salt in production procedure among traditional Atorvastatin calcium
The predicament of noxious material.It, can be without using hydrogen cyanide, hydrohalogenic acid salt etc. by preparation among completely new Atorvastatin calcium
Synthesis compound VI is prepared under the premise of extremely toxic substance, and utilizes VI prepare compound I of compound.It is adopted in whole preparation process
With reagent safety, environmental protection, is a kind of preparation method more suitable for industrialized production.
Specific implementation mode
In order to better understand the present invention, below we the present invention will be further elaborated in conjunction with specific embodiments.
Each embodiment agents useful for same is commercial product unless otherwise indicated.
Embodiment 1
At 0 DEG C, by lithium metal（0.18g）40mL anhydrous ethers are dissolved in, compound ii is slowly added dropwise thereto（2.79g
0.01mol）Diethyl ether solution 10ml, stir at 0 DEG C, generated with white precipitate in reaction, reaction until lithium after the reaction was complete,
It stands, takes the supernatant containing compound III for reacting in next step.
By methylchloroformate（1.09g 0.012mol）It is dissolved in 10ml anhydrous ethers, under conditions of -20 DEG C thereto
The supernatant containing compound III obtained in abovementioned steps is added dropwise（The diethyl ether solution of compound III）, after being added dropwise to complete, rise to
Room temperature（15~25℃）, stir to reaction and terminate.Then it is cooled to 0 DEG C, and 6.5mL is added into the solution after reaction and is saturated chlorine
Change ammonium salt solution, the hydrochloric acid 2.2ml that mass percent is 10% is then added, retains organic layer, is washed with 5% sodium bicarbonate, rotates
Ether is removed, 2.11g compounds Ⅳs are obtained（Purity 93%, yield 70%）.Characterization of The Products data are as follows：1H-NMR (400 MHz,
CDCl3) δ 4.49 – 4.37 (m, 2H), 3.70 (s, 3H), 2.62-2.53 (m, 2H), 2.40-2.32 (m,
2H), 1.86-1.77 (m, 2H), 1.42 (s, 9H), 1.21 (s, 6H). 13C-NMR (100 MHz, CDCl3) δ
172.92, 171.80, 100.80, 81.86, 69.53, 51.87, 42.07, 41.03, 35.33, 28.33,
26.21 .
By compounds Ⅳ（6.25g 0.02mol）With NH3H2O（200mL）/MeOH（200mL）Solution is stirred at room temperature about 16
Hour, after reaction, major part MeOH is removed, is diluted with water and is extracted with DCM.Combined organic layer is washed with brine,
It is dried and concentrated with anhydrous sodium sulfate, obtains compound V（1.45g 85%）.Characterization of The Products data are as follows：1H-NMR (400
MHz, CDCl3) δ 5.61 (s, 2H), 4.49 – 4.36 (m, 1H), 4.16 – 4.04 (m, 1H), 2.65 –
2.56 (m, 1H), 2.56 – 2.47 (m, 1H), 2.43 – 2.36 (m, 1H), 2.34-2.26 (m, 1H),
1.83 – 1.70 (m, 1H), 1.57-1.52 (m, 1H), 1.42 (s, 9H), 1.21 (s, 6H).13C-NMR
(100 MHz, CDCl3) δ 175.73, 172.92, 100.80, 81.86, 73.66, 69.53, 45.59, 41.03,
35.33, 28.33, 26.21。
By compound V（4.31g,0.015mol）It is dissolved in toluene（25mL）In, pyridine is added（0.5mL）And thionyl chloride
（0.5mL）, it is stirred at room temperature overnight, then uses water, sodium bicarbonate aqueous solution and salt water washing respectively, be dried and concentrated.
To compound VI（3.23g 80%）.Characterization of The Products data are as follows：1H-NMR (400 MHz, CDCl3) δ 4.47-4.44 (m,
2H), 2.92-2.88(m, 1H), 2.77-2.70 (m, 1H), 2.60-2.56 (m, 1H), 2.40-2.32 (m,
1H), 2.00-1.92 (m, 1H), 1.82-1.74 (m, 1H), 1.42 (s, 9H), 1.21 (s, 6H).13C-NMR
(100 MHz, CDCl3) δ 172.92, 171.80, 100.80, 81.86, 69.53, 51.87, 42.07, 41.03,
35.33, 28.33, 26.21。
In reaction kettle, compound VI is first added（5g）, acetic acid 50ml adds 10% palladium carbon（0.5g）Acetic acid solution
（5ml）, 20-30 DEG C of hydrogenation 8h.After the completion of reaction, diatomite filtering rotates filtrate, obtains grease.Grease is molten
In 30ml water, pH is adjusted to 8-9 with liquefied ammonia, is then extracted with dichloromethane.By dichloromethane layer separation and with anhydrous sulphur
Sour sodium is dry and rotates, and obtains chemical compounds I（4.62g 91%）.Characterization of The Products data are as follows：1H-NMR (400 MHz,
CDCl3): δ4.23-4.19 (m, 1H),3.99-3.95 (m, 1H), 2.74 (t, J =7.1 Hz, 2H), 2.40-
2.36 (m, 1H),2.27-2.22 (m,1H), 1.58-1.41 (m, 2H),1.40 (s, 9H), 1.31 (s, 6H),
0.89 (s, 9H). 13C-NMR (100 MHz, CDCl3) δ 172.92, 100.80, 81.86, 69.53, 67.23,
41.03, 40.00, 39.23, 35.55, 28.33, 26.21。
Embodiment 2
At 0 DEG C, by lithium metal（0.18g）40mL anhydrous tetrahydro furans are dissolved in, compound ii is slowly added dropwise thereto（2.79g
0.01mol）Tetrahydrofuran solution 10ml, stir at 0 DEG C, generated with white precipitate in reaction, reaction is until lithium has reacted
Quan Hou is stood, and takes the supernatant containing compound III for reacting in next step.
By methylchloroformate（1.09g 0.012mol）It is dissolved in 10ml anhydrous tetrahydro furans.Under conditions of -20 DEG C to
The supernatant containing compound III obtained in abovementioned steps is wherein added dropwise（The tetrahydrofuran solution of compound III）, it is warmed to room temperature
（15~25℃）, stirring, after reaction, 10% hydrochloric acid is then added in addition 6.5mL saturated ammonium chloride solutions at 0 DEG C
2.2ml retains organic layer, is washed with 5% sodium bicarbonate, and revolving removes tetrahydrofuran, obtains 2.05g compounds Ⅳs（Purity 92%,
Yield 68%）.
By compounds Ⅳ（6.25g 0.02mol）With NH3H2O（200mL）/MeOH（200mL）Solution is stirred at room temperature
About 16 hours, after reaction, major part MeOH is removed, is diluted with water and is extracted with DCM.Combined organic layer is washed with salt
It washs, is dried and concentrated with anhydrous sodium sulfate, obtain compound V（1.45g 85%）.
Compound V（4.31g,0.015mol）It is dissolved in toluene（25mL）In, pyridine is added（0.5mL）And thionyl chloride
（0.5mL）, it is stirred at room temperature overnight, then uses water, sodium bicarbonate aqueous solution and salt water washing respectively, be dried and concentrated.
To compound VI（3.23g 80%）.
In reaction kettle, compound VI is first added（5g）, acetic acid 50ml adds 10% platinum carbon（0.5g）Acetic acid solution
（5ml）, 20-30 DEG C of hydrogenation 8h.After the completion of reaction, diatomite filtering rotates filtrate, obtains grease.Grease is molten
In 30ml water, pH is adjusted to 8-9 with liquefied ammonia, is then extracted with dichloromethane.By dichloromethane layer separation and with anhydrous sulphur
Sour sodium is dry and rotates, and obtains chemical compounds I（4.57g 90%）.
Embodiment 3
At 0 DEG C, by lithium metal（0.18g）40mL anhydrous ethers are dissolved in, compound ii is slowly added dropwise thereto（2.79g
0.01mol）Diethyl ether solution 10ml, stir at 0 DEG C, generated with white precipitate in reaction, reaction until lithium after the reaction was complete,
It stands, takes the supernatant containing compound III for reacting in next step.
By methylchloroformate（1.09g 0.012mol）It is dissolved in 10ml anhydrous ethers.Under conditions of -20 DEG C thereto
The supernatant containing compound III obtained in abovementioned steps is added dropwise（The diethyl ether solution of compound III）, it is warmed to room temperature（15~25
℃）, stir, after reaction, saturated ammonium chloride solution be added at 0 DEG C, 10% hydrochloric acid 2.2ml is then added, retains organic
Layer, is washed with 5% sodium bicarbonate, and revolving removes ether, obtains 2.11g compounds Ⅳs（Purity 93%, yield 70%）.
Compounds Ⅳ（6.25g 0.02mol）In, excessive saturation NH is added3/ MeOH solution, is stirred at room temperature about 16
Hour, after reaction, major part MeOH is removed, is diluted with water and is extracted with DCM.Combined organic layer is washed with brine,
It is dried and concentrated with anhydrous sodium sulfate, obtains compound V（1.42g 83.3%）.
Compound V（4.31g,0.015mol）It is dissolved in toluene（25mL）In, pyridine is added（0.5mL）And thionyl chloride
（0.5mL）, it is stirred at room temperature overnight, then uses water, sodium bicarbonate aqueous solution and salt water washing respectively, be dried and concentrated.
To compound VI（3.23g 80%）.
In reaction kettle, compound VI is first added（5g）, formic acid 50ml adds 10% platinum carbon（0.5g）Formic acid solution
（5ml）, 20-30 DEG C of hydrogenation 8h.After the completion of reaction, diatomite filtering rotates filtrate, obtains grease.Grease is molten
In 30ml water, pH is adjusted to 8-9 with liquefied ammonia, is then extracted with dichloromethane.By dichloromethane layer separation and with anhydrous sulphur
Sour sodium is dry and rotates, and obtains chemical compounds I（4.62g 91%）.
Embodiment 4
It is tested according to mode disclosed in embodiment 1-3, unlike embodiment 1-3.In the present embodiment, right respectively
Solvent and reaction temperature in first step reaction are replaced.
We are respectively with the grade ratios of 1,4- dioxane, dichloromethane, toluene, dimethylbenzene and ether and tetrahydrofuran
Example mixed solution, ether and tetrahydrofuran 1:100（Volume ratio）, ether and tetrahydrofuran 100:1（Volume ratio）, toluene and dichloro
Methane 1:100（Volume ratio）, toluene and dichloromethane 100:1（Volume ratio）Etc. ether in solution forms alternative embodiment 1-3
Or tetrahydrofuran, the results show that solution disclosed by the invention may be incorporated for the solvent of first step reaction.
We replace 0 DEG C in the first step with -5 DEG C, -2 DEG C, 2 DEG C, 5 DEG C, 8 DEG C, 10 DEG C respectively and react, and as a result show
Showing can react under the conditions of -5 DEG C~10 DEG C.
Embodiment 5
It is tested according to mode disclosed in embodiment 1-3, unlike embodiment 1-3.In the present embodiment, right respectively
Solvent and reaction temperature in second step reaction are replaced.
We are respectively with -30 DEG C, -28 DEG C, -25 DEG C, -15 DEG C, -13 DEG C, -10 DEG C, -8 DEG C, -5 DEG C, 0 DEG C of replacement second step
In -20 degrees Celsius.
As a result being shown in the range of -30 DEG C to 0 DEG C can react.
According to the reagent being added in the first step, corresponding addition Isosorbide-5-Nitrae-dioxane, dichloromethane in second step respectively
The equal proportion mixed solution of alkane, toluene, dimethylbenzene and ether and tetrahydrofuran, ether and tetrahydrofuran 1:100（Volume
Than）, ether and tetrahydrofuran 100:1（Volume ratio）, toluene and dichloromethane 1:100（Volume ratio）, toluene and dichloromethane
100:1（Volume ratio）Etc. ether or tetrahydrofuran in solution forms alternative embodiment 1-3, the results show that the present invention discloses
Solution may be incorporated for second step reaction solvent.
Embodiment 6
It is tested according to mode disclosed in embodiment 1-3, unlike embodiment 1-3.In the present embodiment, to third
Reaction temperature in step reaction is replaced.
In the present embodiment respectively investigate 15 DEG C, 20 DEG C, 25 DEG C, 30 DEG C, 35 DEG C, 40 DEG C, 45 DEG C, 50 DEG C, 55 DEG C, 60
℃、65℃、70℃、75℃、80℃、85℃、90℃、95℃、100℃。
As a result it may be implemented to react in the range of being shown in 15 DEG C ~ 100 DEG C.
Embodiment 7
It is tested according to mode disclosed in embodiment 1-3, unlike embodiment 1-3.In the present embodiment, to the 4th step
Reaction temperature in reaction is replaced.
Respectively with dichloromethane, 1,2- dichloroethanes, acetonitrile, n,N-Dimethylformamide, dimethyl sulfoxide (DMSO), benzene, diformazan
Benzene, the mixed solution of dichloromethane and toluene, acetonitrile and toluene mixed solution etc. replace the dissolving that toluene is used for compound V.
The results show that solution disclosed in the present invention may be incorporated for the dissolving of compound V.
Pyridine is substituted with 4-dimethylaminopyridine, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide respectively.As a result it shows
Show, solution disclosed in the present invention may be incorporated for being formed the alkaline reaction environment of compound V.
Dichloro is replaced as dehydrating agent using phosphorus oxychloride and thionyl chloride and the arbitrary proportion mixture of phosphorus oxychloride respectively
Sulfoxide, the results show that can obtain compound VI.
Embodiment 8
It is tested according to mode disclosed in embodiment 1-3, unlike embodiment 1-3.In the present embodiment, to compound
The reaction condition of VI prepare compound I is replaced.
Respectively using the mixture of the mixture of platinum carbon, Raney's nickel and palladium carbon and platinum carbon, palladium carbon and Raney's nickel as catalysis
Agent is used for VI prepare compound I of compound.The results show that catalyst disclosed by the invention may be incorporated for VI preparationization of compound
Close object I.
Respectively with the arbitrary mixing ratio of the alcoholic solutions such as methanol, ethyl alcohol, propyl alcohol and formic acid, propionic acid or alcohol and acid solution
The mixed solution that example obtains replaces acetic acid, the results show that solution disclosed by the invention may be incorporated for compound VI as solvent
Prepare compound I.
The above is the specific implementation mode of the present invention.It should be pointed out that for those skilled in the art,
Various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also considered as this hair
Bright protection domain.
Claims (10)
1. the preparation method of Atorvastatin calcium intermediate, it is characterised in that：The synthetic route of this method is as follows：
。
2. the preparation method of Atorvastatin calcium according to claim 1, feature exist：Include the following steps：
The first step：Compound III is obtained by the reaction with synthesis in compound II；
Second step：Under cryogenic conditions, methylchloroformate is mixed with compound III, then increases temperature to room temperature, compound
Compound IV is obtained by the reaction with methylchloroformate in III；
Third walks：Under alkaline condition, compound V is obtained by the reaction in the methanol solution of compound IV and ammonia；
4th step：For compound V under the action of dehydrating agent, dehydration generates compound VI.
3. the preparation method of Atorvastatin calcium according to claim 2, it is characterised in that：It is preferably following in the first step
Any one or several optimum conditions,
First step reaction is that one kind in ether, tetrahydrofuran, 1,4- dioxane, dichloromethane, toluene, dimethylbenzene is molten
Liquid or two kinds optionally and the two or more in the mixed solvents obtained according to the mixing of arbitrary mixed proportion are reacted；Particularly preferably
It is to be reacted in ether or tetrahydrofuran solution；
Reaction temperature is -5-10 DEG C.
4. the preparation method of Atorvastatin calcium according to claim 2, it is characterised in that：It is preferably following in second step
Any one or several optimum conditions,
A. the methylchloroformate is that compound III is added dropwise into methylchloroformate solution with the compound III modes mixed；
B. further include being quenched after the completion of second step reacts, extract, dry, concentration；
C. the cryogenic conditions refer to -30 DEG C ~ 0 DEG C, particularly preferably -20 DEG C；
D. the solvent of methylchloroformate solution is ether, tetrahydrofuran, 1,4- dioxane, dichloromethane, toluene, dimethylbenzene
One or more of the mixed solvent that is mixed to form according to arbitrary mixed proportion, wherein particularly preferred methylchloroformate
The solvent of solution is ether or tetrahydrofuran.
5. the preparation method of Atorvastatin calcium according to claim 2, it is characterised in that：It is preferably following in the third step
Any one or several optimum conditions,
A. third step in be into the organic solution of compound IV be added ammonia methanol solution reacted；
B. after the completion of three-step reaction, further include removing solvent, extract, dry, concentration；
C. the methanol solution of the ammonia is the methanol solution that ammonia is dissolved in the saturated ammonia formed in methanol solution, either
Ammonium hydroxide is mixed to the methanol solution of the ammonia obtained with methanol solution；
D. the reaction temperature of three-step reaction is 15 ~ 100 DEG C.
6. the preparation method of Atorvastatin calcium according to claim 2, it is characterised in that：Compound V is dissolved in organic molten
Agent, under the action of alkaline matter and dehydrating agent, dehydration generates compound VI.
7. the preparation method of Atorvastatin calcium according to claim 6, it is characterised in that：It is preferred that it is following any one or
The several optimum conditions of person：
A. organic solvent it is excellent for dichloromethane, 1,2- dichloroethanes, acetonitrile, n,N-Dimethylformamide, dimethyl sulfoxide (DMSO),
The mixture of one or more of benzene,toluene,xylene arbitrary proportion mixing；
B. alkaline matter be pyridine, 4-dimethylaminopyridine, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide at least
It is a kind of；
C. dehydrating agent is that thionyl chloride, one kind in phosphorus oxychloride or thionyl chloride are mixed with phosphorus oxychloride according to arbitrary proportion
The mixture of acquisition.
8. the preparation method of Atorvastatin calcium according to claim 1, which is characterized in that further include prepared by compound VI
The method of compound I：Compound VI is dissolved in organic solvent, under the effect of the catalyst, is reacted with hydrogen, obtains compound I.
9. the preparation method of Atorvastatin calcium according to claim 8, it is characterised in that：In the organic molten of compound VI
Organic molten solution that catalyst is added in agent solution carries out hydrogenation, after the completion of reaction, filters, and concentration is diluted with water, liquid
Ammonia tune PH is extracted, dry, and concentration obtains corresponding compound I.
10. the preparation method of Atorvastatin calcium according to claim 8, which is characterized in that preferably it is following any one
Or several optimum conditions：
A. the catalyst is the mixture of palladium carbon, platinum carbon, one or two kinds of any of the above ratio of Raney's nickel；Especially
Preferably palladium carbon or platinum carbon；
B. the organic solvent is the alcohols such as methanol, ethyl alcohol, propyl alcohol, formic acid, acetic acid, propionic acid it is one or two kinds of more than
The mixture of arbitrary mixed proportion mixing；Particularly preferably acetic acid；
C. compound VI and hydrogen react under conditions of 20-30 DEG C under the effect of the catalyst.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810653383.0A CN108586427B (en) | 2018-06-22 | 2018-06-22 | Preparation method of atorvastatin calcium intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810653383.0A CN108586427B (en) | 2018-06-22 | 2018-06-22 | Preparation method of atorvastatin calcium intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108586427A true CN108586427A (en) | 2018-09-28 |
| CN108586427B CN108586427B (en) | 2020-08-11 |
Family
ID=63633985
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810653383.0A Active CN108586427B (en) | 2018-06-22 | 2018-06-22 | Preparation method of atorvastatin calcium intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108586427B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114181188A (en) * | 2021-12-08 | 2022-03-15 | 江苏阿尔法药业股份有限公司 | Non-solvation synthesis method of atorvastatin calcium intermediate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107778279A (en) * | 2017-11-13 | 2018-03-09 | 江苏欧信制药有限公司 | A kind of preparation method of Atorvastatin calcium intermediate |
-
2018
- 2018-06-22 CN CN201810653383.0A patent/CN108586427B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107778279A (en) * | 2017-11-13 | 2018-03-09 | 江苏欧信制药有限公司 | A kind of preparation method of Atorvastatin calcium intermediate |
Non-Patent Citations (1)
| Title |
|---|
| FANG-JUN XIONG等: "《An improved process for chiron synthesis of the atorvastatin side》", 《TETRAHEDRON ASYMMETRY》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114181188A (en) * | 2021-12-08 | 2022-03-15 | 江苏阿尔法药业股份有限公司 | Non-solvation synthesis method of atorvastatin calcium intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108586427B (en) | 2020-08-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103880625B (en) | Method for preparing D, L-mandelic acid and derivative of D, L-mandelic acid | |
| CN101462935B (en) | Process for synthesizing alpha-bromoacetophenone compound | |
| CN101863858A (en) | Synthetic method of bentazone | |
| CN101171251A (en) | Process for making aztreonam | |
| CN108586427A (en) | The preparation method of Atorvastatin calcium intermediate | |
| KR101595747B1 (en) | Method for preparing of nafamostat mesilate | |
| Wang et al. | Synthesis of difluorinated β-and γ-amino acids: Investigation of a challenging deoxyfluorination reaction | |
| CN106749071B (en) | A kind of preparation method of aromatics 1,2,4,5- tetrazine compound | |
| US9695125B2 (en) | Method for synthesizing cationic bleach activators via a single-bath reaction | |
| CN105712919A (en) | Application of amide condensing agent in vildagliptin synthetic method | |
| WO2017205622A1 (en) | Method of making benznidazole | |
| CN108299466B (en) | Improved dolutegravir synthesis method | |
| CN111072660B (en) | Simple preparation method of rilibatan | |
| CN102382026A (en) | Environmentally-friendly synthesis process of Aztreonam main ring (3S-trans)-3-amino-4-methyl-2-oxo-1-azetidinyl sulfonic acid | |
| CN105884644A (en) | Advantage forms and preparation method of neutral endopeptidase inhibitor salt | |
| CN106946724B (en) | The synthetic method of monoamine base inhibitor class intermediate 2- acetylaminohydroxyphenylarsonic acid 2- benzyl malonic acid mono ethyl ester | |
| CN102603543B (en) | Preparation method of mexiletine hydrochloride | |
| CN107129440B (en) | A kind of total synthesis method of natural products (+)-negamycin | |
| CN111892544A (en) | 3- (aminomethyl) -4- (4-fluorophenyl) piperazine-1-carboxylic acid tert-butyl ester and synthesis method thereof | |
| CN106279114B (en) | A kind of synthetic method of Taladegib | |
| CN107089928A (en) | The synthetic method of N Boc L propargylglycines | |
| CN108640861A (en) | " one kettle way " that alkynyl amide mediates prepares macrolide | |
| CN103254268A (en) | Process for preparing dutasteride | |
| CN109983011A (en) | The manufacturing method of polymerizable compound | |
| CN115073252B (en) | 13C Mexaxetine and synthesis method of 13C phenacetin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 223800 No.5 Yanshan Road, eco Chemical Technology Industrial Park, Suqian City, Jiangsu Province Patentee after: Jiangsu alpha Pharmaceutical Co.,Ltd. Address before: 223800 No.5 Yanshan Road, eco Chemical Technology Industrial Park, Suqian City, Jiangsu Province Patentee before: ALPHA PHARMACEUTICAL Co.,Ltd. JIANGSU PROVINCE |