CN103694228B - A method of preparing Pitavastatin Calcium key intermediate - Google Patents
A method of preparing Pitavastatin Calcium key intermediate Download PDFInfo
- Publication number
- CN103694228B CN103694228B CN201310698009.XA CN201310698009A CN103694228B CN 103694228 B CN103694228 B CN 103694228B CN 201310698009 A CN201310698009 A CN 201310698009A CN 103694228 B CN103694228 B CN 103694228B
- Authority
- CN
- China
- Prior art keywords
- compound
- zinc
- preparation
- reaction
- pitavastatin 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.)
- Active
Links
Classifications
-
- 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
Abstract
The invention belongs to field of pharmaceutical chemistry technology, and in particular to a kind of preparation method of Pitavastatin Calcium key intermediate.This method includes being formed with machine zincon with high activity zinc and 2 cyclopropyl 4 (4 fluorophenyl), 3 quinoline methylene bromide.The organic zinc reagent and (3R, 5S) 6 oxo 3, Witting reactions occur for 5 dihydroxy, 3,5 O isopropylidene hecanoic acid t-butyl esters, generate (3R, 5S, 6E) 7 [2 cyclopropyl 4 (4 fluorophenyl) quinoline, 3 base] 3,53,5 O isopropylidenes of dihydroxy, 6 heptene tert-butyl acrylate, Pitavastatin Calcium key intermediate can be obtained using recrystallization in it.Synthetic method provided by the present invention has the features such as purity of E is high, simple process, high income.
Description
Technical field
The present invention relates to a kind of methods that high activity organic zinc reagent prepares Pitavastatin Calcium key intermediate.
Background technology
Pitavastatin Calcium is HMG-CoA reductase inhibitor, is blood lipid-lowering medicine.Pitavastatin Calcium is Japanese Nissan chemistry
Industrial Co., Ltd develops, and is listed in Japan in July, 2003, is used for the treatment of hypercholesterolemia, trade name
" LIVALO ", preparation specification are the thin membrane coated tablet of 1mg and 2mg.
By being retrieved to the prior art, wherein in patent EP304063, E-3- [2- cyclopropyl -4- (4- fluorophenyls) -3-
Quinoline -2- methacrylaldehyde docked with ethyl acetoacetate after through reduction, split, obtain Pitavastatin Calcium at salt.This method step is long,
Technique is harsh, and first docks and split afterwards, one is screened in four kinds of optical isomers into salt, yield is very low.
In patent WO2007/132482, by relatively short reaction step, it is prepared for cutting down him under mild conditions
Spit of fland or its salt.It is reacted by Wittig, makes 2- cyclopropyl -4- (4- fluorophenyls) -3- quinolylmethyls phosphonium salts and (3R, 5S) -6- oxygen
Generation -3,5- dihydroxy -3,5-O- isopropylidene hecanoic acid t-butyl esters are reacted, and the intermediate with dioxane part is made
Afterwards, then after converting it into the amine salt form of the intermediate with dihydroxy part, Pitavastatin or its salt are prepared.Party's legal system
Standby intermediate purity is not high, and has remained the triphenylphosphinc oxide that Wittig reactions generate.And the post-processing side of intermediate
Method uses into the form of ammonium salt, increases the complexity of processing, and final purity of E is not also high.
In Chinese patent CN102174039B, with (4R, 6S) -6- methylols -2,2- dimethyl-1,3-dioxane -
4- tert-butyl acetates are raw material, with 1,1'- (Isosorbide-5-Nitrae-phenylene) bis- (1H-TETRAZOLE -5- mercaptan) and diisopropyl azodiformate
In tetrahydrofuran carry out Mitsunobu reactions, obtain sulphones using oxidation reaction, finally with 2- cyclopropyl -4- (4-
Fluorophenyl) Pitavastatin Calcium key intermediate is obtained by the reaction in quinoline-3-formaldehyde under alkaline environment.The method processing step compared with
It is long；There are deep cooling reaction, condition harsher；And multiple column chromatography is have passed through, it is less efficient.
Invention content
The present invention is directed to deficiencies of the prior art, provides a kind of preparation side of Pitavastatin Calcium key intermediate
Method, solve existing Pitavastatin Calcium Z formula isomers remain it is more, isolate and purify the technical problem that difficulty is big and yield is relatively low.
The technical solution adopted in the present invention is as follows：
The high activity zinc that 2- cyclopropyl -4- (4- fluorophenyls) -3- quinoline methylene bromides (II) and brand-new are got ready is in ethers
Oxidative addition occurs in organic solvent, organic zinc reagent (III) is made.In ether organic solvent, organic zinc reagent (III)
Occur under alkaline environment with (3R, 5S) -6- oxo -3,5- dihydroxy -3,5-O- isopropylidenes hecanoic acid t-butyl esters (IV)
Wittig reacts, and generates (3R, 5S, 6E) -7- [2- cyclopropyl -4- (4- fluorophenyls) quinoline -3- bases] -3,5- dihydroxy -3,5-
O- isopropylidene -6- heptene tert-butyl acrylates (I).Compound (I) recrystallizes in C1-C4 alcohols solvents, and purity of E can be obtained
Qualified Pitavastatin Calcium key intermediate.
The structural formula of the above related compound is as follows：
The ether solvent is ether, tetrahydrofuran, dioxane, isopropyl ether.Wherein preferred tetrahydrofuran.
The oxidative addition is as shown in following formulas：
The high activity zinc can be lithium/zinc bromide combination, and naphthalene lithium/zinc bromide combines, activated metal zinc, wherein it is preferred that
Naphthalene lithium/zinc bromide combination.
The prior art may be used in the preparation of wherein high activity zinc, and [Li Lezhen, organic zinc reagent is in organic conjunction for bibliography
Several applications in, China Science ＆ Technology University's doctoral thesis].
Wherein, compound (II) and the molar ratio of high activity zinc are 1:1~1:2, preferably 1:1.5-1:2；Reaction temperature is
20-100 DEG C, it is in reflux state that reaction temperature, which needs holding system, and the optimum solvent is tetrahydrofuran according to the present invention, should
It is best that temperature, which selects 65-75 DEG C,.
Wittig reactions under the alkaline environment, refer in ether organic solvent, occur in the presence of alkali
Reaction, reaction equation are as follows：
The alkali is alkali metal salt.Can be sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, preferably potassium carbonate.
Wherein, the molar ratio of compound (IV) and compound (III) is 1:0.8~1:2, preferably 1:1.0-1:1.2；Reaction
Temperature is 10-50 DEG C, and preferable temperature is 20-40 DEG C；
The C1-C4 alcohols solvents mainly select in methanol, ethyl alcohol, isopropanol, propyl alcohol, n-butanol, preferably methanol,
Ethyl alcohol.
C1-C4 alcohols solvents are 2-10 times, preferably 4-8 times of compound (I) when wherein recrystallizing.
The specific synthetic route of synthetic method of the present invention is as follows：
Beneficial effects of the present invention are：By means of the invention it is also possible to relatively mild reaction condition, locate after simple
Reason mode obtains that purity is good, the high Pitavastatin Calcium key intermediate of purity of E.
Specific implementation mode
According to following embodiments, the present invention can be better understood from.Specific material proportion, technique described in embodiment
Condition and result are merely to illustrate the present invention, without that should will not limit the present invention described in detail in claims.
Embodiment 1：
The preparation of lithium naphthalene reagent：
Under nitrogen protection, lithium metal (0.4g, 60mmol) is added in anhydrous naphthalene (2.6g, 20mmol), temperature control 20-25
DEG C stirring 2h obtain lithium naphthalene reagent.
The preparation of organic zinc reagent (III), reaction equation are as follows：
Operating procedure：Under nitrogen protection, compound (II) (10.7g, 30mmol), nothing are added into 250ml reaction bulbs
Water tetrahydrofuran 50ml, stirring are cooled to 10-20 DEG C, and zinc bromide (13.5g, 60mmol) is added portionwise, and stir 10 minutes, instill
Above-mentioned naphthalene lithium reagent is heated to reflux (65-75 DEG C), is stirred to react 5-6h after reaction temperature stabilization.Gained reaction solution is
Organic zinc reagent (III).
The preparation of compound (I), reaction equation are as follows：
Operating procedure：To addition K in organic zinc reagent (III)2CO3(12.4g, 90mmol), 0-10 DEG C of stirring of temperature control；It will change
After conjunction object (IV) (7.8g, 30mmol) is dissolved in the clarification of tetrahydrofuran (15ml) stirring and dissolving, above-mentioned organic zinc reagent (III) is instilled
In, about 0.5h is dripped off.It is warming up to 25-30 DEG C and is stirred to react 16h, HPLC tracks reaction end.After reaction, temperature control 10-20
DEG C, distilled water 130ml is added dropwise, reaction is quenched in stirring 1h.Filter, successively use distilled water (25ml × 3), absolute methanol (20ml ×
3) filter cake is washed three times.It is dried in vacuo 4h at 50 DEG C of filter cake, obtains compound (I) white solid (13.9g, 27mmol).
Compound (I) refines：
Operating procedure：Compound (I) is placed in 250ml there-necked flasks, absolute methanol 83ml is added, is heated to complete molten reflux
5min, the lower slow cooling of filtrate stirring continue to be cooled to 10 DEG C, insulated and stirred 2h, filter, filter cake is used to 35-45 DEG C of stirring 1h
Cold methanol (25ml × 3) is washed and starched three times.It is dried in vacuo 4h at 50 DEG C of filter cake and obtains refined compound (I) white solid
(10.4g, 20mmol), yield 66.7%.
Embodiment 2：
The preparation of organic zinc reagent (III), reaction equation are as follows：
Operating procedure：Under nitrogen protection, compound (II) (10.7g, 30mmol), nothing are added into 250ml reaction bulbs
Water tetrahydrofuran 50ml, stirring are cooled to 10-20 DEG C, and zinc bromide (13.5g, 60mmol) is added, and stir 10 minutes, are added portionwise
Lithium metal (0.4g, 60mmol) is heated to reflux (65-75 DEG C), is stirred to react 5-6h after reaction temperature stabilization.Gained is anti-
It is organic zinc reagent (III) to answer liquid.
The preparation of compound (I), reaction equation are as follows：
Operating procedure：To potassium carbonate (12.4g, 90mmol) is added in organic zinc reagent (III), 0-10 DEG C of temperature control stirs；It will
After compound (IV) (7.8g, 30mmol) is dissolved in the clarification of tetrahydrofuran (15ml) stirring and dissolving, above-mentioned organic zinc reagent is instilled
(III) in, about 0.5h is dripped off.It is warming up to 25-30 DEG C and is stirred to react 16h, HPLC tracks reaction end.After reaction, temperature control
10-20 DEG C, distilled water 130ml is added dropwise, reaction is quenched in stirring 1h.It filters, uses distilled water (25ml × 3), absolute methanol successively
(20ml × 3) wash filter cake three times.Be dried in vacuo 4h at 50 DEG C of filter cake, obtain compound (I) white solid (10.8g,
20.9mmol)。
Compound (I) refines：
Operating procedure：Compound (I) is placed in 250ml there-necked flasks, absolute methanol 65ml is added, is heated to complete molten reflux
5min, the lower slow cooling of filtrate stirring continue to be cooled to 10 DEG C, insulated and stirred 2h, filter, filter cake is used to 35-45 DEG C of stirring 1h
Cold methanol (20ml × 3) is washed and starched three times.At 50 DEG C of filter cake be dried in vacuo 4h obtain refined compound (I) white solid (7.2g,
13.9mmol), yield 46.3%.
Embodiment 3：
The preparation of lithium naphthalene reagent：
Under nitrogen protection, lithium metal (0.4g, 60mmol) is added in anhydrous naphthalene (2.6g, 20mmol), temperature control 20-25
DEG C stirring 2h obtain lithium naphthalene reagent.
The preparation of organic zinc reagent (III), reaction equation are as follows：
Operating procedure：Under nitrogen protection, compound (II) (10.7g, 30mmol), nothing are added into 250ml reaction bulbs
Water tetrahydrofuran 50ml, stirring are cooled to 10-20 DEG C, and zinc bromide (13.5g, 60mmol) is added portionwise, and stir 10 minutes, instill
Above-mentioned naphthalene lithium reagent is heated to reflux (65-75 DEG C), is stirred to react 5-6h after reaction temperature stabilization.Gained reaction solution is
Organic zinc reagent (III).
The preparation of compound (I), reaction equation are as follows：
Operating procedure：To addition K in organic zinc reagent (III)2CO3(12.4g, 90mmol), 0-10 DEG C of stirring of temperature control；It will change
After conjunction object (IV) (7.8g, 30mmol) is dissolved in the clarification of tetrahydrofuran (15ml) stirring and dissolving, above-mentioned organic zinc reagent (III) is instilled
In, about 0.5h is dripped off.It is warming up to 25-30 DEG C and is stirred to react 16h, HPLC tracks reaction end.After reaction, temperature control 10-20
DEG C, distilled water 130ml is added dropwise, reaction is quenched in stirring 1h.Filter, successively use distilled water (25ml × 3), absolute methanol (20ml ×
3) filter cake is washed three times.It is dried in vacuo 4h at 50 DEG C of filter cake, obtains compound (I) white solid (13.9g, 27mmol).
Compound (I) refines：
Operating procedure：Compound (I) is placed in 250ml there-necked flasks, absolute methanol 130ml is added, is heated to complete molten reflux
5min, the lower slow cooling of filtrate stirring continue to be cooled to 10 DEG C, insulated and stirred 2h, filter, filter cake is used to 35-45 DEG C of stirring 1h
Cold methanol (25ml × 3) is washed and starched three times.At 50 DEG C of filter cake be dried in vacuo 4h obtain refined compound (I) white solid (8.4g,
16mmol), yield 54.2%.
Claims (6)
1. a kind of method preparing Pitavastatin Calcium key intermediate, it is characterised in that operated according to following processing step：
The high activity zinc that 2- cyclopropyl -4- (4- fluorophenyls) -3- quinoline methylene bromides (II) and brand-new are got ready is organic in ethers
Oxidative addition occurs in solvent, organic zinc reagent (III) is made；In ether organic solvent, organic zinc reagent (III) with
Under alkaline environment Wittig occurs for (3R, 5S) -6- oxo -3,5- dihydroxy -3,5-O- isopropylidenes hecanoic acid t-butyl esters (IV)
It is different to generate (3R, 5S, 6E) -7- [2- cyclopropyl -4- (4- fluorophenyls) quinoline -3- bases] -3,5- dihydroxy -3,5-O- Asia for reaction
Propyl -6- heptene tert-butyl acrylate (I)；Compound (I) recrystallizes in C1-C4 alcohols solvents, and Pitavastatin Calcium key can be obtained
Intermediate；
The oxidative addition is as shown in following formulas：
Wherein, compound (II) and the molar ratio of high activity zinc are 1:1~1:2, reaction temperature is 20-100 DEG C；
Wittig reactions under the alkaline environment, refer in dimethyl sulfoxide solvent, occur in the presence of alkali anti-
It answers, reaction equation is as follows：
Wherein, the molar ratio of compound (IV) and compound (III) is 1:0.8~1:2, reaction temperature is 10-50 DEG C,
The high activity zinc is lithium/zinc bromide combination or naphthalene lithium/zinc bromide combination.
2. preparation method as described in claim 1, characterized in that the high activity zinc is naphthalene lithium/zinc bromide combination.
3. preparation method as described in claim 1, characterized in that the ether solvent is ether, tetrahydrofuran, dioxy six
Ring, isopropyl ether.
4. preparation method as described in claim 1, characterized in that the alkali is alkali metal salt, and the alkali metal salt is hydrogen
Sodium oxide molybdena, potassium hydroxide, sodium carbonate, potassium carbonate.
5. preparation method as described in claim 1, characterized in that the C1-C4 alcohols solvents are in methanol, ethyl alcohol, isopropyl
It is selected in alcohol, propyl alcohol, n-butanol.
6. preparation method as described in claim 1, characterized in that C1-C4 alcohols solvents are the 2- of compound (I) when recrystallization
10 times.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310698009.XA CN103694228B (en) | 2013-12-18 | 2013-12-18 | A method of preparing Pitavastatin Calcium key intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310698009.XA CN103694228B (en) | 2013-12-18 | 2013-12-18 | A method of preparing Pitavastatin Calcium key intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103694228A CN103694228A (en) | 2014-04-02 |
| CN103694228B true CN103694228B (en) | 2018-08-28 |
Family
ID=50355917
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310698009.XA Active CN103694228B (en) | 2013-12-18 | 2013-12-18 | A method of preparing Pitavastatin Calcium key intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103694228B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110407818A (en) * | 2019-07-18 | 2019-11-05 | 安庆恩聚生物医药科技有限公司 | A kind of preparation method of Pitavastatin Calcium intermediate |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0304063A2 (en) * | 1987-08-20 | 1989-02-22 | Nissan Chemical Industries Ltd. | Quinoline type mevalonolactones |
| CN1653074A (en) * | 2002-05-22 | 2005-08-10 | 艾夫西亚有限公司 | Compound and processes for the preparation and use thereof |
| CN1656077A (en) * | 2001-06-06 | 2005-08-17 | 布里斯托尔-迈尔斯斯奎布公司 | Process for preparing chiral diol sulfones and dihydroxy acid HMG CoA reductase inhibitors |
| WO2007132482A2 (en) * | 2006-05-17 | 2007-11-22 | Manne Satyanarayana Reddy | Novel process for the preparation of pitavastatin and its pharmaceutically acceptable salts |
| CN101195575A (en) * | 2006-12-08 | 2008-06-11 | 西北师范大学 | process for producing (E)-3-dimethoxy-4'-acetoxy diphenyl ethylene |
| CN102174039A (en) * | 2011-03-10 | 2011-09-07 | 上海交通大学 | Preparation method of high-optical-purity pitavastatin calcium key intermediate |
-
2013
- 2013-12-18 CN CN201310698009.XA patent/CN103694228B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0304063A2 (en) * | 1987-08-20 | 1989-02-22 | Nissan Chemical Industries Ltd. | Quinoline type mevalonolactones |
| CN1656077A (en) * | 2001-06-06 | 2005-08-17 | 布里斯托尔-迈尔斯斯奎布公司 | Process for preparing chiral diol sulfones and dihydroxy acid HMG CoA reductase inhibitors |
| CN1653074A (en) * | 2002-05-22 | 2005-08-10 | 艾夫西亚有限公司 | Compound and processes for the preparation and use thereof |
| WO2007132482A2 (en) * | 2006-05-17 | 2007-11-22 | Manne Satyanarayana Reddy | Novel process for the preparation of pitavastatin and its pharmaceutically acceptable salts |
| CN101195575A (en) * | 2006-12-08 | 2008-06-11 | 西北师范大学 | process for producing (E)-3-dimethoxy-4'-acetoxy diphenyl ethylene |
| CN102174039A (en) * | 2011-03-10 | 2011-09-07 | 上海交通大学 | Preparation method of high-optical-purity pitavastatin calcium key intermediate |
Non-Patent Citations (1)
| Title |
|---|
| 金属锌在有机合成反应中的应用;李国平，等;《有机化学》;20021231;第22卷(第11期);第801-806页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103694228A (en) | 2014-04-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5545118B2 (en) | Method for producing nitrile compound, carboxylic acid compound or carboxylic acid ester compound | |
| KR102145272B1 (en) | Process for making isoquinoline compounds | |
| CN105153010B (en) | The preparation method of HMG-CoA reductase inhibitor and its intermediate | |
| EP2998299B1 (en) | Preparation method of azoxystrobin | |
| CN106543191A (en) | A kind of ticagrelor preparation technology | |
| US20030087930A1 (en) | Process for preparing 2-(4-chlorobenzolamino)-3[ (1h)-quinolinon-4-yl] propionic acid | |
| CN103694228B (en) | A method of preparing Pitavastatin Calcium key intermediate | |
| ES2629313T3 (en) | Preparation procedure of 1 - ([1,3] dioxolan-4-ylmethyl) -1 H -pyrazol-3-ylamine | |
| WO2002063028A1 (en) | Process for producing (3r,5s)-(e)-7-[2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl]-3,5-dihydroxyhept-6-enic acid esters | |
| JPWO2015119261A1 (en) | Method for producing rosuvastatin calcium and intermediates thereof | |
| CN109574999B (en) | Preparation method of pitavastatin calcium intermediate | |
| JP4783998B2 (en) | Preparation of (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid | |
| CN105461606B (en) | The preparation method of high-purity Lei Dipawei intermediates | |
| CN103044339A (en) | Preparation method of rosuvastatin calcium intermediate | |
| WO2014051077A1 (en) | Method for producing nitrogen-containing heterocyclic compound of high purity | |
| CN110092721A (en) | A kind of pyruvate synthesis preparation method | |
| CN109574998B (en) | Synthetic method of pitavastatin calcium intermediate | |
| KR102529680B1 (en) | Method for synthesizing nebivolol and intermediate compounds thereof | |
| JP2013544787A (en) | Method for preparing azaindazole derivatives | |
| CN110218179A (en) | A kind of environment-friendly preparation method of the chloro- 3- nitropyridine of 4- amino -2- | |
| CN103044361A (en) | Preparation method of (2R,3S)-epoxidation amino-benzene butane | |
| CN109836341B (en) | Preparation method of salicylamine acetate | |
| JP2010180186A (en) | New asymmetric reducing agent, and method for producing optically active tetrahydroisoquinoline derivative by using the same | |
| CN106854201B (en) | Purification method of rosuvastatin calcium intermediate | |
| CN105272954A (en) | Preparation method of 6-substituted methyl-4-hydroxyltetrahydropyran-2-one and derivative thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |