CN103613582A - Rosuvastatin lactone - Google Patents
Rosuvastatin lactone Download PDFInfo
- Publication number
- CN103613582A CN103613582A CN201310607280.8A CN201310607280A CN103613582A CN 103613582 A CN103613582 A CN 103613582A CN 201310607280 A CN201310607280 A CN 201310607280A CN 103613582 A CN103613582 A CN 103613582A
- Authority
- CN
- China
- Prior art keywords
- methyl
- fluorophenyl
- sec
- propyl
- pyrimidine
- 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.)
- Pending
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of rosuvastatin lactone. The chemical formula of the rosuvastatin lactone is C22H26FN3O5S; the rosuvastatin lactone is prepared by taking fluorobenzaldehyde, methyl isobutyrylacetate, urea and cuprous chloride as raw materials through a series of reactions such as condensation, oxidation, reduction, substitution, and the like, so that a final product rosuvastatin lactone is obtained. The rosuvastatin lactone disclosed by the invention is an economic, security, high-purity and high-yield route, and suitable for industrial production.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of novel method of preparing Rosuvastain statin lactone.
Background technology
Rosuvastain statin lactone is the third generation statins of complete synthesis single enantiomer, belong to HMG-CoA reductase inhibitor, can reduce low density cholesterol, total cholesterol, triglyceride level and the apoB concentration of rising, simultaneously the concentration of increasing high density cholesterol.Can be used for the complex therapy of primary hypercholesterolemia and mixed type lipodystrophy disease and the familial hypercholesterolemia that isozygotys.
Though this product has the total pharmacophoric group dihydroxy heptyl acid moieties of statins, all the other structures in molecule are totally different with other similar drugs, therefore lipid lowering properties is not identical yet.Through a large amount of clinical trials, confirm, the effect of this product reduction LDL-C, rising HDL-C is better than other statins (comprise and be acknowledged as now the Zarator that effect is the strongest) of oneself listing.And it acts on onset time also faster than Zarator, can make obviously the blood fat disorder patient of more different sick types reach the fixed index of U.S.'s " NCEP (National Cholesterol Education Program; NCEP) ", so clinical meaning is great.
It is starting raw material that this route be take p-Fluorobenzenecarboxaldehyde and isobutyryl methyl acetate; through condensation and cyclization, oxidation, replacement sulfonylation, reduction, bromination, phosphine, contracting, give up, go the reactions such as protection, hydrolysis salifying (branch line obtains through hydrolysis, oxidation) to obtain Rosuvastain statin lactone; route is relatively short; easy to operate; process stabilizing; cost is low, and yield is high, is applicable to suitability for industrialized production.
The operational path three wastes of the present invention are processed simple, do not use heavy metal, have more environment-friendly property.Its objective is the Rosuvastain statin lactone of an economy, safety, high purity, high yield synthetic route is provided, be suitable for large-scale industrialization and produce.
Summary of the invention
The chemical molecular formula of Rosuvastain statin lactone is C
22h
26fN
3o
5s, its structural formula is:
Described Rosuvastain statin lactone preparation method comprises following steps:
Rosuvastain statin lactone synthetic route is: take fluorobenzaldehyde, isobutyryl methyl acetate, urea, cuprous chloride is raw material, through condensation reaction, obtain 4-(4-fluorophenyl)-6-sec.-propyl-5-methoxycarbonyl 1,4-2 (1H)-dihydropyrimidinonesand (I); Secondly in reactor, add 65～68% nitric acid, Sodium Nitrite, add intermediate compound I at 101---125 ℃ in batches, through oxidizing reaction, obtain [4-(4-fluorophenyl)-2-hydroxyl-6-sec.-propyl-5-methoxycarbonyl pyrimidine (II); Then take n-butyl acetate, intermediate II, Anhydrous potassium carbonate is raw material, nitrogen protection, and successively add Tosyl chloride, methylsulfonyl methylamine, salt of wormwood to be substituted to react and to obtain [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl is amino) pyrimidine-5-yl] methyl-formiate (III); Take toluene and intermediate III as raw material again, heated and stirred makes entirely molten, nitrogen protection is cooling, drip molten the rolling through reduction reaction of toluene of the diisobutyl aluminium hydride (DIBAL-H) of 1.5mol/L, obtain [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl is amino) pyrimidine-5-yl] methyl alcohol (IV); In reactor, add methylene dichloride and intermediate compound IV, drip phosphorus tribromide through bromo-reaction, obtain N-[5-brooethyl-4-(4-fluorophenyl)-6-sec.-propyl one pyrimidine-2-base]-N-methyl Toluidrin (V); In intermediate V, add toluene heating entirely molten again, add phenylbenzene methoxy base phosphine, be substituted reaction, obtain N-[5-(phenylbenzene phosphinylidyne methyl)-4-(4-fluorophenyl)-6-sec.-propyl one pyrimidine-2-base]-N-methyl Toluidrin (VI); VI by add tetrahydrofuran (THF) and drip NaHMDS through phosphine react (6-" and 2-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl is amino) pyrimidine-5-yl] a vinyl J-(4R; 6S) 1; 2-dimethyl-[1, a 3] dioxan-4-yl) tert.-butyl acetate (VII); Finally in reactor, add intermediate VII, acetonitrile, reaction, adds solid sodium chloride, stirs, and dissolves, and separatory aftertreatment obtains the finished product Rosuvastain statin lactone.
What we invented is the route of a complete synthesis Rosuvastain statin lactone, and synthesizing of its main ring is simple, workable, be applicable to very much workshop and amplify production, and the processing of the operational path three wastes is simple, does not use heavy metal, has more environment-friendly property.
Embodiment
Below by embodiment, further describe the complete synthesis of Rosuvastain statin lactone.
1,4-(4-fluorophenyl)-6-sec.-propyl-5-methoxycarbonyl-3,4-2 (1H)-dihydropyrimidinonesand (L) synthetic
In reactor, add p-Fluorobenzenecarboxaldehyde (500g), isobutyryl methyl acetate (860g), urea 200g, cuprous chloride, methyl alcohol, sulfuric acid, be heated to reflux.Ice-water bath is cooling, suction filtration after continuing to stir, and the methyl alcohol drip washing of gained solid, loft drier obtains white crystal 1460.17g, yield 98.7% after drying.
2, [synthesizing of 4-(4-fluorophenyl)-2-hydroxyl-6-sec.-propyl-5-methoxycarbonyl pyrimidine (II)
In reactor, add 65～68% nitric acid, Sodium Nitrite, add intermediate compound I at 10～25 ℃ in batches, add common need, continue reaction between 10～20 ℃, TLC detection reaction is complete.In reaction solution, add water, then drip sodium hydroxide solution tune pH, note temperature control.Cooling, suction filtration after continuing to stir, gained solid washes with water, and loft drier obtains light yellow solid 1396.49g, yield 95.9% after drying.
3, [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl-formiate (III) is synthetic
In reactor, add n-butyl acetate, intermediate II, Anhydrous potassium carbonate, nitrogen protection, adds Tosyl chloride, reacting by heating, and TLC detection reaction is complete.Add methylsulfonyl methylamine, salt of wormwood, reflux, TLC detects and still has minute quantity raw material unreacted complete.Cooling, be poured into water, stir, standing, aftertreatment, loft drier is dried to obtain white solid 2193.91g, yield 93.8%.
4, [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl is amino) pyrimidine-5-yl] methyl alcohol (IV) is synthetic
In reactor, add toluene and intermediate III, heated and stirred makes entirely molten, and nitrogen protection is cooling, drips the toluene solution of the diisobutyl aluminium hydride (DIBAL-H) of 1.5mol/L, and temperature control drips off and continues reaction, and TLC detection reaction is complete.Aftertreatment, dry white solid 1743.77g, yield 96.1%.
5, N-[5-brooethyl-4-(4-fluorophenyl)-6-sec.-propyl-pyrimidine-2-base]-N-methyl Toluidrin (V) synthetic
In reactor, add methylene dichloride and Shen mesosome IV, drip phosphorus tribromide, TLC detection reaction is complete.After aftertreatment, obtain white solid 1877.48g, yield 95.6%.
6, N-[5-(phenylbenzene phosphinylidyne methyl)-4-(4-fluorophenyl)-6-sec.-propyl-pyrimidine-2-base]-N-methyl Toluidrin (VI) synthetic
Up walk in the intermediate VI of gained and add toluene heating entirely molten, add phenylbenzene methoxy base phosphine, be heated to reaction, TLC detects and has responded.Aftertreatment, vacuum drying oven is dried to obtain white solid 2026.Og, yield 89.3%.
7, (6-" 2-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] a vinyl J mono-(4R, 6S)-2,2-dimethyl-[1,3] dioxan-4-yl)-tert.-butyl acetate (VII) synthetic
In reactor, add main chain, tetrahydrofuran (THF), stir, thermosol is clear a little, and under nitrogen protection, liquid nitrogen is cold, drips NaHMDS, and temperature control drips complete insulation reaction, drips the toluene solution of side chain, and temperature control drips Bi Fanying to finishing.Aftertreatment obtains product 1577.6g, yield 90.3%.
8, Rosuvastain statin lactone is synthetic
In reactor, add intermediate VII, acetonitrile, l drips 1M hydrochloric acid, and reaction is to complete.Cooling lower dropping 1M sodium hydroxide, reaction is to complete.Under cooling, slowly drip 1MHC1, adjust pH, add solid sodium chloride, stir, dissolve, separatory, aftertreatment obtains white solid 1673.34g, yield 96.5%.Total yield is 63.5%, optical purity ee>99.5%.
Claims (8)
1. a Rosuvastain statin lactone, is characterized in that: its chemical molecular formula is C
22h
26fN
3o
5s, its structural formula is:
Described Rosuvastain statin lactone preparation method comprises following steps:
Take fluorobenzaldehyde, isobutyryl methyl acetate, urea, cuprous chloride is raw material, through condensation reaction, obtains 4-(4-fluorophenyl)-6-sec.-propyl-5-methoxycarbonyl-3,4-2 (1H)-dihydropyrimidinonesand (I); Secondly in reactor, add 65～68% nitric acid, Sodium Nitrite, add intermediate work at 10～25 ℃ in batches, through oxidizing reaction, obtain [4-(4-fluorophenyl)-2-hydroxyl-6-sec.-propyl-5-methoxycarbonyl pyrimidine (II); Then take n-butyl acetate, intermediate II, Anhydrous potassium carbonate is raw material, nitrogen protection, and successively add Tosyl chloride, methylsulfonyl methylamine, salt of wormwood to be substituted to react and to obtain [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl is amino) pyrimidine-5-yl] methyl-formiate (I I I); Take toluene and intermediate III as raw material again, heated and stirred makes entirely molten, nitrogen protection is cooling, the toluene solution of the diisobutyl aluminium hydride (DIBAL-H) of dropping 1.5mol/L, through reduction reaction, obtains [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl one N mono-methylsulfonyl is amino) pyrimidine one 5 one bases] methyl alcohol (IV); In reactor, add methylene dichloride and intermediate compound IV, drip phosphorus tribromide through bromo-reaction, obtain N-[5-brooethyl-4-(4-fluorophenyl)-6-sec.-propyl one pyrimidine-2-base]-N-methyl Toluidrin (V); In intermediate V, add toluene heating entirely molten again, add people's phenylbenzene methoxy base phosphine, be substituted reaction, obtain N-[5-(phenylbenzene phosphinylidyne methyl)-4-(4-fluorophenyl)-6-sec.-propyl-pyrimidine-2-base]-N-methyl Toluidrin (VI); VI reacts to obtain (6-F2-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N monomethyl-N-methylsulfonyl is amino) pyrimidine-5-yl by adding tetrahydrofuran (THF) and dripping NaHMDS through phosphine]-vinyl J-(4R, 6S)-2,2-dimethyl-[1,3] dioxan-4-yl)-tert.-butyl acetate (VII); Finally in reactor, add intermediate VII, acetonitrile, reaction, adds solid sodium chloride, stirs, and dissolves, and separatory aftertreatment obtains the finished product Rosuvastain statin lactone.
2. Rosuvastain statin lactone according to claim 1, its feature exists: the preparation method of Rosuvastain statin lactone is that to take fluorobenzaldehyde, isobutyryl methyl acetate, urea, cuprous chloride be raw material, through condensation reaction, prepare 4-(4-fluorophenyl)-6-sec.-propyl-5-methoxycarbonyl-3,4-2 (1H)-dihydropyrimidinonesand (I).
3. according to the Rosuvastain statin lactone described in claim l, its feature exists: the preparation method of Rosuvastain statin lactone adds 65～68% nitric acid, Sodium Nitrite in reactor, at 10～25 ℃, add intermediate work in batches, through oxidizing reaction, obtain [4-(4-fluorophenyl)-2-hydroxyl-6-sec.-propyl-5-methoxycarbonyl pyrimidine (II).
4. according to the Rosuvastain statin lactone described in claim l; its feature exists: the preparation method of Rosuvastain statin lactone is that to take n-butyl acetate, intermediate II, Anhydrous potassium carbonate be fat material; nitrogen protection, and successively add Tosyl chloride, methylsulfonyl methylamine, salt of wormwood to be substituted to react and to obtain [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl is amino) pyrimidine-5-yl] methyl-formiate (III).
5. according to the Rosuvastain statin lactone described in claim l; its feature exists: the preparation method of Rosuvastain statin lactone is that to take toluene and intermediate III be raw material; heated and stirred makes entirely molten; nitrogen protection is cooling; the toluene solution of the diisobutyl aluminium hydride (DIBAL-H) of dropping 1.5mol/L, through reduction reaction, obtains [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl is amino) pyrimidine-5-yl] methyl alcohol (IV).
6. Rosuvastain statin lactone according to claim 1, its feature exists: the preparation method of Rosuvastain statin lactone adds methylene dichloride and intermediate compound IV in reactor, drip phosphorus tribromide through bromo-reaction, obtain N-[5-brooethyl-4-(4-fluorophenyl)-6-sec.-propyl one pyrimidine-2-base]-N-methyl Toluidrin (V).
7. according to the Rosuvastain statin lactone described in claim l, its feature exists: the preparation method of Rosuvastain statin lactone is by adding toluene heating entirely molten in intermediate V, add phenylbenzene methoxy base phosphine, be substituted reaction, obtain N-[5-(phenylbenzene phosphinylidyne methyl)-4-(4-fluorophenyl)-6-sec.-propyl one pyrimidine-2-base]-N-methyl Toluidrin (VI).
8. Rosuvastain statin lactone according to claim 1; its feature exists: the preparation method of Rosuvastain statin lactone reacts to obtain 6-[2-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-first 2 bases-N-methylsulfonyl is amino) pyrimidine-5-yl by adding tetrahydrofuran (THF) and drip NaHMDS in intermediate VI through phosphine]-vinyl J-(4R; 6S)-2; 2-dimethyl-[1,3] dioxane-4-yl)-tert.-butyl acetate (VII).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310607280.8A CN103613582A (en) | 2013-11-25 | 2013-11-25 | Rosuvastatin lactone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310607280.8A CN103613582A (en) | 2013-11-25 | 2013-11-25 | Rosuvastatin lactone |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103613582A true CN103613582A (en) | 2014-03-05 |
Family
ID=50164312
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310607280.8A Pending CN103613582A (en) | 2013-11-25 | 2013-11-25 | Rosuvastatin lactone |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103613582A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104311517A (en) * | 2014-10-17 | 2015-01-28 | 上海应用技术学院 | Polysubstituted phenanthrene ring statin lactone dehydrated compounds and application thereof |
| CN106008372A (en) * | 2016-03-16 | 2016-10-12 | 江苏悦兴药业有限公司 | Preparation method and key intermediate of dacomitinib |
| CN106397335A (en) * | 2016-08-31 | 2017-02-15 | 湖北祥云(集团)化工股份有限公司 | Preparation method of rosuvastatin intermediate |
| CN107445992A (en) * | 2017-06-19 | 2017-12-08 | 浙江美诺华药物化学有限公司 | A kind of synthetic method of Rosuvastatin Calcium intermediate |
| CN108997324A (en) * | 2018-08-21 | 2018-12-14 | 南京欧信医药技术有限公司 | The preparation method of rosuvastain calcium intermediate |
-
2013
- 2013-11-25 CN CN201310607280.8A patent/CN103613582A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104311517A (en) * | 2014-10-17 | 2015-01-28 | 上海应用技术学院 | Polysubstituted phenanthrene ring statin lactone dehydrated compounds and application thereof |
| CN106008372A (en) * | 2016-03-16 | 2016-10-12 | 江苏悦兴药业有限公司 | Preparation method and key intermediate of dacomitinib |
| CN106008372B (en) * | 2016-03-16 | 2019-01-15 | 江苏悦兴药业有限公司 | A kind of preparation method and its key intermediate for replacing Buddhist nun up to grammeter |
| CN106397335A (en) * | 2016-08-31 | 2017-02-15 | 湖北祥云(集团)化工股份有限公司 | Preparation method of rosuvastatin intermediate |
| CN107445992A (en) * | 2017-06-19 | 2017-12-08 | 浙江美诺华药物化学有限公司 | A kind of synthetic method of Rosuvastatin Calcium intermediate |
| CN108997324A (en) * | 2018-08-21 | 2018-12-14 | 南京欧信医药技术有限公司 | The preparation method of rosuvastain calcium intermediate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103613582A (en) | Rosuvastatin lactone | |
| CN101948438A (en) | Novel method for preparing rosuvastatin calcium | |
| CN106632033A (en) | Preparation method of lenvatinib | |
| CN105732619A (en) | Synthesizing method of 5,6,7,8-tetrahydropyridino-[2,3-d]pyrimidine compound | |
| CN112574112B (en) | Method for synthesizing N-substituted 2H-indazole compound through oxidation | |
| CN105085520A (en) | 3-(2-nitro-1-phenylethyl)-2-(2-phenyl-imidazo[1,2-alpha] pyridine) compound | |
| CN115466212B (en) | 2-trifluoromethyl quinoline compound and synthetic method and application thereof | |
| CN101967120A (en) | Preparation method of 2-p-chlorobenzyl pyridine | |
| CN107118215A (en) | A kind of preparation method for treating breast cancer medicines Rui Boxini intermediates | |
| CN108997209B (en) | Preparation method of regorafenib | |
| CN106336378B (en) | Preparation method of quinoline-2-formic ether series | |
| AU2014219681B2 (en) | Process for producing pyridazinone compound and production intermediates thereof | |
| CN104478799B (en) | The preparation method of 1,4-diallyl isoquinolin | |
| CN110156672B (en) | Preparation method of semicarbazide compound and application of prepared compound | |
| CN107011288A (en) | A kind of preparation method of aripiprazole intermediate 1 (2,3 dichlorophenyl) piperazine hydrochloride | |
| CN112174949A (en) | Quinolizinone compound and preparation method thereof | |
| CN107188909B (en) | Method for synthesizing indole-substituted or ferrocene-substituted azaarene | |
| CN105777631B (en) | A kind of synthetic method of the bromo- 8- difluoro-methoxies -1,4- dihydroquinoline -3- carboxylic acid, ethyl esters of 1- cyclopropyl -4- oxos -7- | |
| CN104557738A (en) | Green synthesis method of 4(3H)-quinazolinone | |
| CN101555248B (en) | Method for preparing poly-substituted 1, 5-naphthyridine compound | |
| CN102558145B (en) | Method for preparing balofloxacin | |
| CN104910033A (en) | Method for preparing 5-aminolevulinic acid hydrochloride | |
| CN113185428B (en) | Synthesis method of 4-methyl-3-oxo-valeronitrile | |
| CN109553543A (en) | A kind of synthetic method of N, N- dimethylamino ethyl acrylate | |
| CN112441961B (en) | Synthetic method of 3-pyrroline-2-ketone compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20140305 |