CN106938996A - A kind of preparation method of Atorvastatin calcium intermediate - Google Patents
A kind of preparation method of Atorvastatin calcium intermediate Download PDFInfo
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- CN106938996A CN106938996A CN201610004301.0A CN201610004301A CN106938996A CN 106938996 A CN106938996 A CN 106938996A CN 201610004301 A CN201610004301 A CN 201610004301A CN 106938996 A CN106938996 A CN 106938996A
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- atorvastatin calcium
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- calcium intermediate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
The present invention relates to a kind of preparation method of Atorvastatin calcium intermediate, the preparation method while Atorvastatin calcium intermediate yield is improved, the post-processing approach of Atorvastatin calcium intermediate is simple, operating process simplifies, the production cycle shortens, organic solvent consumption reduction, production cost reduction, production operation when dangerous reduction.This method comprises the following steps：1) reacted using amine ester and diketone as initiation material in mixed solvent, the mixed solvent is volume ratio 1：13 normal heptane and tetrahydrofuran, often adds 5 8ml mixed solvents using 1g amine ester；2) the gained reaction solution of concentration step 1 removes mixed solvent, obtains Atorvastatin calcium crude intermediate；3) step 2 products therefrom is added after the dissolving clarification of the ethanol of recrystallisation solvent 1, adds the purified water of recrystallisation solvent 2, cool, centrifugal drying.
Description
Technical field
The present invention relates to a kind of preparation method of Atorvastatin calcium intermediate, more particularly to a kind of post-processing step is simply high
The preparation method of purity Atorvastatin calcium intermediate.
Background technology
Atorvastatin calcium, English name：Atorvastatin Calcium, chemical name：[R- (R, R)] -2- (4- fluorophenyls) -
β, beta-dihydroxy -5- (1- Methylethyls) -3- phenyl -4- [(aniline) carbonyl] -1- hydrogen-pyrroles's -1- enanthic acid calcium trihydrates, are high conjunctions
Into, High Purity, high selectivity suppress HMG-CoA reductase medicine, developed by Pfizer, be the third generation he
Spit of fland class medicine.It is mainly used in treating the preventing and treating of hypercholesterolemia, high fat of blood and coronary heart disease and headstroke.
The synthetic route of current Atorvastatin calcium is using amine ester and diketone as initiation material synthetic intermediate condensation product, Ran Houzai
Atorvastatin calcium is further synthesized by raw material of intermediate condensate, wherein：Point of amine ester described in the present patent application file
Shown in the following reaction equation of minor, it is ((4R-cis) -2,2- dimethyl -6- (2- the aminoethyls)-tertiary fourth of 1,3- dioxane -4- acetic acid
Ester) abbreviation；It is ((±)-α-isobutyryl shown in the following reaction equation of the molecular formula of diketone described in this paper application documents
- γ-oxo-N, β-diphenyl -4- fluorobenzene butyramide) abbreviation；The molecular formula of intermediate condensate described in this paper application documents is such as
Shown in lower reaction equation, it is ((4R-cis) -6- [2- [2- (4- fluorophenyls) -5- (1- isopropyls) -3- phenyl -4- [(aniline) carbonyl] -1H-
Pyrroles -1- bases] ethyl] -2,2- dimethyl-1,3-dioxane -4- tert-butyl acetates) and abbreviation, composition principle is such as in the prior art
Lower reaction equation：
The synthetic route of Atorvastatin calcium intermediate condensate is reacted using amine ester and diketone as initiation material in the prior art,
After reaction terminates, the process steps of intermediate condensate are cumbersome, complex operation, production cycle length, organic solvent amount disappear
Consume that larger, cost is higher, yield is low, the problem of there is production security.Such as：Plus toluene extraction, then through alkali cleaning, pickling,
Salt is washed, then adds activated carbon decolorizing, then filter activity charcoal, solvent distillation, adds ethanol and n-hexane crystallization, and centrifugation is dry
Atorvastatin calcium intermediate condensate, weight yield 110% are obtained after dry.
The content of the invention
To overcome the defect of prior art, the invention provides a kind of preparation method of Atorvastatin calcium intermediate.The preparation
Method is while Atorvastatin calcium intermediate yield is improved, and the post-processing approach of Atorvastatin calcium intermediate is simple, behaviour
Danger when making process simplification, production cycle shortening, organic solvent consumption reduction, production cost reduction, production operation drops
It is low.
A kind of preparation method of Atorvastatin calcium intermediate, comprises the following steps：
1st, using mass ratio as 1：1-1.5 amine ester and diketone react for initiation material according to formulas below in mixed solvent,
The mixed solvent is volume ratio 1：1-3 normal heptane and tetrahydrofuran, often adds 5-8ml mixed solvents using 1g amine ester；
2nd, the gained reaction solution of concentration step 1 removes mixed solvent, obtains Atorvastatin calcium crude intermediate；
3rd, step 2 products therefrom is added after the dissolving clarification of the ethanol of recrystallisation solvent 1, adds the purified water of recrystallisation solvent 2,
It is cooled to 40-75 DEG C to be crystallized, preferably 50 DEG C, is often used in centrifugal drying, wherein step 1 in 1g amine esters step 3 just
Use 3-7ml ethanol and 1-4ml purified waters, preferably 4ml ethanol and 3ml purified waters.
A kind of preparation method of Atorvastatin calcium intermediate, wherein the mass ratio of the amine ester and diketone is 1：1-1.25.
A kind of preparation method of Atorvastatin calcium intermediate, wherein the mixed solvent is volume ratio 1：2-2.5 normal heptane
And tetrahydrofuran.
A kind of preparation method of Atorvastatin calcium intermediate, often 6-7.5ml mixing is added wherein in step 1 using 1g amine ester
Solvent.
A kind of preparation method of Atorvastatin calcium intermediate, the condition wherein reacted described in step 1 is heating reflux reaction
30-50h, preferably 36-40h.
Compared with prior art, the present invention has the advantages that：
1st, no longer extraction, alkali cleaning, pickling and salt are washed in step, simplify production procedure, shorten the production cycle, are reduced
The consumption and sewage discharge of organic solvent, realizes clean manufacturing, dangerous reduction during production operation；
2nd, amine ester and diketone special ratios, mixed solvent specific composition, recrystallisation solvent specific composition, crystallization temperature etc. are passed through
The selection of condition, the weight yield for making product Atorvastatin calcium intermediate condensate is more than 125%, and the HPLC of product is pure
Spend for 99.0%, the weight yield of product improves more than 15%, and cost is greatly lowered.
Brief description of the drawings
Fig. 1 is the flow chart of the preparation method of Atorvastatin calcium intermediate of the present invention.
Embodiment
Below in conjunction with the accompanying drawings, the embodiment to the present invention is described in detail, it is to be understood that the protection model of the present invention
Enclose and do not limited by embodiment.
Embodiment 1
Amine ester 16g and diketone 20g is added in 250ml reaction bulbs and 34ml normal heptanes and 68ml tetrahydrofuran groups is dissolved in
Into mixed solvent in, temperature rising reflux react 40 hours, after completion of the reaction concentration of reaction solution remove mixed solvent, obtain Ah
Atorvastatin calcium crude intermediate, plus 110ml ethanol make after crude intermediate dissolving clarification, add purified water 64ml, cooling
Material is separated out to 50 DEG C, centrifugal filtration obtains intermediate 25.1g, the weight yield relative to diketone is 125.5%, HPLC
Purity is 99.0%.
Embodiment 2
Amine ester 16g and diketone 20g is added in 250ml reaction bulbs and 34ml normal heptanes and 85ml tetrahydrofuran groups is dissolved in
Into mixed solvent in, temperature rising reflux react 36 hours, after completion of the reaction concentration of reaction solution remove mixed solvent, obtain Ah
Atorvastatin calcium crude intermediate, plus 64ml ethanol make after crude intermediate dissolving clarification, add purified water 48ml, cooling
Material is separated out to 75 DEG C, centrifugal filtration obtains intermediate condensate 25.3g, relative to the weight yield 126.5% of diketone,
HPLC purity is 99.0%.
Embodiment 3
Amine ester 16g and diketone 24g is added in 250ml reaction bulbs and 34ml normal heptanes and 85ml tetrahydrofuran groups is dissolved in
Into mixed solvent in, temperature rising reflux react 50 hours, after completion of the reaction concentration of reaction solution remove mixed solvent, obtain Ah
Atorvastatin calcium crude intermediate, plus 80ml ethanol make after crude intermediate dissolving clarification, add purified water 32ml, cooling
Material is separated out to 70 DEG C, centrifugal filtration obtains intermediate condensate 25.2g, relative to the weight yield 126.0% of diketone,
HPLC purity is 99.0%.
Embodiment 4
Amine ester 16g and diketone 20g is added in 250ml reaction bulbs and 38ml normal heptanes and 76ml tetrahydrofuran groups is dissolved in
Into mixed solvent in, temperature rising reflux react 40 hours, after completion of the reaction concentration of reaction solution remove mixed solvent, obtain Ah
Atorvastatin calcium crude intermediate, plus 64ml ethanol make after crude intermediate dissolving clarification, add purified water 48ml, cooling
Material is separated out to 50 DEG C, centrifugal filtration obtains intermediate condensate 26.6g, relative to the weight yield 133.0% of diketone,
HPLC purity is 99.0%.
Disclosed above is only the specific embodiment of the present invention, and still, the present invention is not limited to this, the skill of any this area
What art personnel can think change should all fall into protection scope of the present invention.
Claims (8)
1. a kind of preparation method of Atorvastatin calcium intermediate, it is characterised in that comprise the following steps：
1) using mass ratio as 1：1-1.5 amine ester and diketone react for initiation material according to formulas below in mixed solvent,
The mixed solvent is volume ratio 1：1-3 normal heptane and tetrahydrofuran, often adds 5-8ml mixed solvents using 1g amine ester；
2) the gained reaction solution of concentration step 1 removes mixed solvent, obtains Atorvastatin calcium crude intermediate；
3) step 2 products therefrom is added after the dissolving clarification of the ethanol of recrystallisation solvent 1, adds the purified water of recrystallisation solvent 2,
It is cooled to 40-75 DEG C to be crystallized, centrifugal drying, often using just using 3-7ml in 1g amine esters step 3 wherein in step 1
Ethanol and 1-4ml purified waters.
2. the preparation method of Atorvastatin calcium intermediate according to claim 1, it is characterised in that the amine ester and
The mass ratio of diketone is 1：1-1.25.
3. the preparation method of Atorvastatin calcium intermediate according to claim 1 or 2, it is characterised in that described mixed
Bonding solvent is volume ratio 1：2-2.5 normal heptane and tetrahydrofuran.
4. the preparation method of Atorvastatin calcium intermediate according to claim 1 or 2, it is characterised in that step 1
In often add 6-7.5ml mixed solvents using 1g amine ester.
5. the preparation method of Atorvastatin calcium intermediate according to claim 1 or 2, it is characterised in that step 1
Described in the condition reacted be heating reflux reaction 30-50h.
6. the preparation method of Atorvastatin calcium intermediate according to claim 5, it is characterised in that institute in step 1
The condition for stating reaction is heating reflux reaction 36-40h.
7. the preparation method of Atorvastatin calcium intermediate according to claim 1 or 2, it is characterised in that be cooled to
50 DEG C are crystallized.
8. the preparation method of Atorvastatin calcium intermediate according to claim 1 or 2, it is characterised in that step 1
In often using just using 4ml ethanol and 3ml purified waters in 1g amine esters step 3.
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| CN201610004301.0A CN106938996B (en) | 2016-01-05 | 2016-01-05 | A kind of preparation method of Atorvastatin calcium intermediate |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108218759A (en) * | 2018-01-12 | 2018-06-29 | 天方药业有限公司 | A kind of Atorvastatin calcium preparation method |
| CN109232353A (en) * | 2018-10-09 | 2019-01-18 | 河南师范大学 | A kind of preparation method of Atorvastatin calcium condensation product |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003024959A1 (en) * | 2001-09-14 | 2003-03-27 | EGIS Gyógyszergyár Rt. | Polymorphs of a 1-pyrrole derivative, intermediate for the preparation of atorvastatin |
| WO2007088553A1 (en) * | 2006-01-31 | 2007-08-09 | Jubilant Organosys Limited | Process for the preparation of amorphous atorvastatin calcium salt |
| EP2075246A1 (en) * | 2007-12-27 | 2009-07-01 | M. J. Institute of Research | A process for preparation of amorphous form of atorvastatin hemi-calcium salt |
| CN102344401A (en) * | 2011-09-15 | 2012-02-08 | 景德镇市富祥药业有限公司 | Method for preparing amorphous atorvastatin calcium |
| CN102766136A (en) * | 2012-08-07 | 2012-11-07 | 浙江宏元药业有限公司 | Method for preparing atorvastatin calcium intermediate |
-
2016
- 2016-01-05 CN CN201610004301.0A patent/CN106938996B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003024959A1 (en) * | 2001-09-14 | 2003-03-27 | EGIS Gyógyszergyár Rt. | Polymorphs of a 1-pyrrole derivative, intermediate for the preparation of atorvastatin |
| WO2007088553A1 (en) * | 2006-01-31 | 2007-08-09 | Jubilant Organosys Limited | Process for the preparation of amorphous atorvastatin calcium salt |
| EP2075246A1 (en) * | 2007-12-27 | 2009-07-01 | M. J. Institute of Research | A process for preparation of amorphous form of atorvastatin hemi-calcium salt |
| CN102344401A (en) * | 2011-09-15 | 2012-02-08 | 景德镇市富祥药业有限公司 | Method for preparing amorphous atorvastatin calcium |
| CN102766136A (en) * | 2012-08-07 | 2012-11-07 | 浙江宏元药业有限公司 | Method for preparing atorvastatin calcium intermediate |
Non-Patent Citations (1)
| Title |
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| 王芬华，等: "Paal-Knorr反应合成2,5-二甲基吡咯衍生物", 《安徽工程大学学报》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108218759A (en) * | 2018-01-12 | 2018-06-29 | 天方药业有限公司 | A kind of Atorvastatin calcium preparation method |
| CN109232353A (en) * | 2018-10-09 | 2019-01-18 | 河南师范大学 | A kind of preparation method of Atorvastatin calcium condensation product |
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| CN106938996B (en) | 2019-11-19 |
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