CN105622522A - Synthetic method of rosuvastatin calcium key intermediate - Google Patents
Synthetic method of rosuvastatin calcium key intermediate Download PDFInfo
- Publication number
- CN105622522A CN105622522A CN201410718131.3A CN201410718131A CN105622522A CN 105622522 A CN105622522 A CN 105622522A CN 201410718131 A CN201410718131 A CN 201410718131A CN 105622522 A CN105622522 A CN 105622522A
- Authority
- CN
- China
- Prior art keywords
- fluorophenyl
- isopropyl
- reaction
- times amount
- synthetic method
- 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
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a synthetic method of a rosuvastatin calcium key intermediate. The synthetic method particularly comprises the following steps: carrying out a condensation reaction between fluoroacetophenone and ethyl isobutyrate under the condition of using sodium as alkali by using isopropyl alcohol as a solvent to prepare 1-(4-fluorophenyl)-4-methyl amyl-1,3-diketone; then carrying out a ring closing reaction between the 1-(4-fluorophenyl)-4-methyl amyl-1,3-diketone and methylguanidine hydrochloride by using isopropanol as a solvent to obtain 4-(4-fluorophenyl)-6-isopropyl-N-methyl pyrimidine-2-amine; carrying out a substitution reaction between the 4-(4-fluorophenyl)-6-isopropyl-N-methyl pyrimidine-2-amine and methanesulfonyl chloride by using dichloromethane as a solvent to obtain 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methanesulfonyl) amino] pyrimidine; finally, carrying out a Vilsmeier reaction between the 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methanesulfonyl) amidogen] pyrimidine and DMF (Dimethyl Formamide) as well as phosphoryl chloride to obtain a target compound. The method disclosed by the invention has the advantages of being simple to operate, low in raw material price, high in availability of used raw materials, mild in reaction conditions, low in equipment requirements and production cost, easy for scale production and the like, and has significance industrial application value.
Description
Technical field
The present invention relates to rosuvastain calcium, be specifically related to the synthetic method of rosuvastain calcium key intermediate.
Background technology
Rosuvastain calcium, it it is the statins of new generation of complete synthesis single enantiomer, the low density cholesterol of rising, T-CHOL, triglyceride and apoB concentration can be reduced, the concentration of increasing high density cholesterol simultaneously, can be used for primary hypercholesterolemia and the Comprehensive Treatment of mixed type dyslipidemia and the familial hypercholesterolemia that isozygotys, belong to HMG-CoA reductase inhibitor.
5-(formoxyl)-4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl) amino] pyrimidine is an important intermediate of synthesizing rosuvastatin spit of fland calcium, its structural formula following (Formulas I):
European patent EP 521471 discloses the synthetic method of a kind of rosuvastain calcium, the preparation method wherein relating to described intermediate, and the key step of this technique is as follows:
This technique employs the huge DDQ of toxicity (2,3-bis-chloro-5,6-dicyano Isosorbide-5-Nitrae benzoquinone), is unfavorable for the health of operator, does not meet the idea of development of Green Chemistry; Additionally, this process recovery ratio is low, it is unfavorable for large-scale production.
Summary of the invention
The problems referred to above existed for prior art and defect, it is an object of the invention to provide the synthetic method of a kind of rosuvastain calcium intermediate Formulas I, and the method is low to operator ' s health harm, it is easy to accomplish large-scale production.
The object of the present invention is achieved like this:
A kind of synthetic method of rosuvastain calcium intermediate,
Described intermediate has a structure that
Employing following steps synthesize:
1) with to fluoro acetophenone and ethyl isobutyrate when sodium makes alkali, make solvent with isopropanol, prepare 1-(4-fluorophenyl)-4-methylpent-1,3-diketone through condensation reaction;
2) 1-(4-fluorophenyl)-4-methylpent-1,3-diketone makes solvent with methylguanidine hydrochloride with isopropanol, occurs ring closure reaction to obtain 4-(4-fluorophenyl)-6-isopropyl-N-methylpyrimidine-2-amine;
3) 4-(4-fluorophenyl)-6-isopropyl-N-methylpyrimidine-2-amine and mesyl chloride are with dichloromethane for solvent, occur substitution reaction to obtain 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl) amino] pyrimidine;
4) 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl) amino] pyrimidine occurs Vilsmeier to be obtained by reacting target compound with DMF and phosphorus oxychloride.
Described step 1) reaction temperature be preferred with 30��85 DEG C, wherein the mol ratio of fluoro acetophenone, ethyl isobutyrate and sodium hydride is preferred with 1: 0.9��1.1: 1.5��4.
Described step 2) reaction temperature be 60��90 DEG C and be preferred, wherein 1-(4-fluorophenyl)-4-methylpent-1, the mol ratio of 3-diketone, methylguanidine hydrochloride and potassium hydroxide is 1: 1��1.5: 2.5��4.
Described step 3) reaction temperature be 0��25 DEG C, wherein the mol ratio of 4-(4-fluorophenyl)-6-isopropyl-N-methylpyrimidine-2-amine, triethylamine and mesyl chloride is 1: 3��5: 1��1.2.
Described step 4) reaction temperature be 80��108 DEG C; Wherein the mol ratio of 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl) amino] pyrimidine, DMF and phosphorus oxychloride is 1: 1��1.1: 1��2.5.
The operation of described Vilsmeier reaction is addition phosphorus oxychloride in reaction vessel, it is warming up to 90 DEG C, the mixed solution of dropping 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl) amino] pyrimidine and DMF, dropwises maintenance 98��103 DEG C reaction.
A kind of synthetic method of rosuvastain calcium intermediate Formulas I, it is characterised in that: adopt following operation:
Under nitrogen protection, the sodium (amount of substance is unit) of 1.5��4 times amount is dissolved in isopropanol alcoholic solution, the lower ethyl isobutyrate (amount of substance is unit) to fluoro acetophenone (amount of substance is unit) and 1��1.5 times amount adding 1 times amount of stirring, at 0��90 DEG C of stirring reaction 4��8h, last separated purification obtains 1-(4-fluorophenyl)-4-methylpent-1,3-diketone;
By 1-(4-the fluorophenyl)-4-methylpent-1 of 1 times amount, 3-diketone (amount of substance is unit), the methylguanidine hydrochloride (amount of substance is unit) of 1��1.5 times amount and the potassium hydroxide (amount of substance is unit) of 2.5��4 times amount are dissolved in aqueous isopropanol, stirring reaction 12h at 60��90 DEG C, last separated purification obtains 4-(4-fluorophenyl)-6-isopropyl-N-methylpyrimidine-2-amine;
By 4-(4-fluorophenyl)-6-isopropyl-N-methylpyrimidine-2-amine (amount of substance is unit) of 1 times amount, the triethylamine (amount of substance is unit) of 3��5 times amount and the mesyl chloride (amount of substance is unit) of 1��1.2 times amount are dissolved in dichloromethane, stirring reaction 12��36h at 0��25 DEG C, last separated purification obtains 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl) amino] pyrimidine;
By 1��2.5 times amount phosphorus oxychloride (amount of substance is unit) in reaction bulb, drip the N of 1 times amount 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl) amino] pyrimidine (amount of substance is unit) and 1��1.1 times amount, dinethylformamide mixed solution, 98��108 DEG C of stirring reactions 4��6 hours, it is finally separating purification and obtains target compound.
Technique effect
1. the present invention with to fluoro acetophenone and ethyl isobutyrate for initiation material, raw material sources are extensive, cheap and easy to get. Cyclization process does not have the DDQ using toxicity huge, has been effectively ensured the safety of operator, has met the theory of Green Chemistry.
2. technique does not have to use the much more expensive material such as 4-methylmorpholine N-oxide, TPAP (crossing ruthenic acid tetrapropyl ammonium), DIBAL-H, effectively reduce production cost.
3. reaction condition of the present invention is gentle, and energy consumption is low, it is not necessary to special consersion unit, and simple to operate, it may be achieved one pot carries out, it is easy to large-scale production.
4. solvent for use of the present invention can realize synchronizing to reclaim, and has not only saved cost, has also protected environment.
In a word, adopt the inventive method can meet the requirement of industrialized mass production rosuvastain calcium intermediate (Formulas I) better, there is significance industrial application value.
Detailed description of the invention
Finally it is necessary described herein: following example are served only for technical scheme is described in further detail; it is not intended that limiting the scope of the invention; those skilled in the art is without departing from the spirit and scope of the present invention, it should various modifications may be made and change. Therefore protection scope of the present invention should be considered as appending claims limited range.
Embodiment 1:1-(4-fluorophenyl)-4-methylpent-1, the synthesis of 3-diketone (compound IV)
150g isopropanol is added in the there-necked flask of 0.5L, after be dividedly in some parts 6.9g sodium, strong agitation sodium dissolves after completely, and fluorine-based 1-Phenylethanone. 13.81g (0.1mol) and ethyl isobutyrate 11.62g (0.1mol) are dissolved in the solution of 80g isopropanol by dropping. Reactant liquor, in 82 DEG C of back flow reaction 6h, is cooled to room temperature, and stirring is overnight. Large-tonnage product precipitates out, and filters to obtain off-white color finished product, and 40 DEG C of convection oven are dried to constant weight, obtain 18g, yield 86%. Nuclear magnetic data (1HNMR, 500MHz, interior mark TMS, solvent C DCl3) is as follows: 1.30 (d, J=7.0Hz, 6H, CH3), 2.61 (m, 1H, CH), 4.15 (s, 1H, CH2), 7.18��7.12 (m, 2H, Ar-H), 7.93��7.87 (m, 2H, Ar-H).
The synthesis of embodiment 2:4-(4-fluorophenyl)-6-isopropyl-N-methylpyrimidine-2-amine (Compound II per I)
Adding 10.4g (0.05mol) compound IV, 6g (0.055mol) methylguanidine hydrochloride, 8.4g (0.15mol) potassium hydroxide, 100ml isopropanol in the there-necked flask of 250ml, temperature rising reflux reacts overnight. Reaction terminates, and decompression is distilled off isopropanol, naturally cools to 10 DEG C, filters, a small amount of isopropanol drip washing filter cake, and gained filter cake is dried to constant weight in 50 DEG C of vacuum drying ovens. Obtain pale solid 11.4g, yield 93%. Nuclear magnetic data (1HNMR, 500MHz, interior mark TMS, solvent DMSO) is as follows: 1.25 (d, J=6.8Hz, 6H, CH3), 2.98 (d, 3H, CH3), 3.18 (m, 1H, CH), 4.98 (s, 1H, NH), 6.71 (s, 1H, Ar-H), 7.16��7.10 (m, 2H, Ar-H), 7.52��7.47 (m, 2H, Ar-H).
The synthesis of embodiment 3:4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl) amino] pyrimidine (Compound II per)
Under nitrogen protection, in the there-necked flask of 250ml, add 9.8g (0.04mol) Compound II per I and 100ml dichloromethane, be cooled to 5 DEG C. , add 12.1g (0.12mol) triethylamine, stirring reaction half an hour. In reactant liquor, it is slowly added dropwise 5.5g (0.048mol) mesyl chloride is dissolved in the solution of 5ml dichloromethane, continue stirring reaction 12h in 0��25 DEG C. Reaction terminates, and adds 20ml dichloromethane, 30ml purification, and concentrated hydrochloric acid adjusts pH=2��3, and layering obtains organic layer. With 50ml saturated common salt water washing once, 10g anhydrous sodium sulfate dries gained organic layer, filters. Decompression precipitation removes dichloromethane, adds 50ml methanol in residue, and stirring is cooled to 5 DEG C, filters, dry, obtains 11g white solid II, productivity 85%. Nuclear magnetic data (1HNMR, 500MHz, interior mark TMS, solvent DMSO) is as follows: 1.26 (d, J=6.8Hz, 6H, CH3), 3.29 (m, 1H, CH), 3.51 (s, 3H, N-CH3), 3.55 (s, 3H, CH3SO2), 6.85 (s, 1H, Ar-H), 7.18��7.12 (m, 2H, Ar-H), 7.93��7.87 (m, 2H, Ar-H).
The synthesis of embodiment 4:5-(formoxyl)-4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl) amino] pyrimidine (compound I)
9.2g (0.06mol) phosphorus oxychloride is added in the there-necked flask of 100ml, open stirring and be warming up to 90 DEG C, dropping 9.7g (0.03mol) Compound II per and 2.4g (0.033mol) N, dinethylformamide mixed solution, continues to control reaction temperature 98��108 DEG C and reacts about 4��6 hours after dropwising. Reaction is cooled to room temperature after terminating, and is added to 50ml water by system drop, dropwises a large amount of solid and precipitates out, filters, and filter cake washes with water to weakly acidic pH. Gained filter cake adds 20ml re-crystallizing in ethyl acetate, filters, dry, obtains 7.6g white solid I, productivity 72%. Nuclear magnetic data (1HNMR, 500MHz, interior mark TMS, solvent C DCl3) as follows: 1.34 (d, J=6.8Hz, 6H, CH3), 3.55 (s, 3H, NCH3), 3.64 (s, 3H, CH3SO2), 3.99 (m, 1H, CH), 7.20��7.27 (m, 2H, Ar-H), 7.61��7.66 (m, 2H, Ar-H), 9.98 (s, 1H, CHO).
Embodiment 5
Under nitrogen protection, the sodium (amount of substance is unit) of 1.5 times amount is dissolved in isopropanol alcoholic solution, the lower ethyl isobutyrate (amount of substance is unit) to fluoro acetophenone (amount of substance is unit) and 1 times amount adding 1 times amount of stirring, at 0 DEG C of stirring reaction 8h, last separated purification obtains 1-(4-fluorophenyl)-4-methylpent-1,3-diketone;
By 1-(4-the fluorophenyl)-4-methylpent-1 of 1 times amount, 3-diketone (amount of substance is unit), the methylguanidine hydrochloride (amount of substance is unit) of 1 times amount and the potassium hydroxide (amount of substance is unit) of 2.5 times amount are dissolved in aqueous isopropanol, stirring reaction 12h at 60 DEG C, last separated purification obtains 4-(4-fluorophenyl)-6-isopropyl-N-methylpyrimidine-2-amine;
By 4-(4-fluorophenyl)-6-isopropyl-N-methylpyrimidine-2-amine (amount of substance is unit) of 1 times amount, the triethylamine (amount of substance is unit) of 3 times amount and the mesyl chloride (amount of substance is unit) of 1 times amount are dissolved in dichloromethane, stirring reaction 36h at 0 DEG C, last separated purification obtains 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl) amino] pyrimidine;
By 1��2.5 times amount phosphorus oxychloride (amount of substance is unit) in reaction bulb, drip the N of 1 times amount 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl) amino] pyrimidine (amount of substance is unit) and 1 times amount, dinethylformamide mixed solution, 98 DEG C of stirring reactions 6 hours, it is finally separating purification and obtains target compound. Structural confirmation, gained target compound is identical with embodiment 4 end-product structure.
Embodiment 6
Under nitrogen protection, the sodium (amount of substance is unit) of 4 times amount is dissolved in isopropanol alcoholic solution, the lower ethyl isobutyrate (amount of substance is unit) to fluoro acetophenone (amount of substance is unit) and 1��1.5 times amount adding 1 times amount of stirring, at 90 DEG C of stirring reaction 4h, last separated purification obtains 1-(4-fluorophenyl)-4-methylpent-1,3-diketone;
By 1-(4-the fluorophenyl)-4-methylpent-1 of 1 times amount, 3-diketone (amount of substance is unit), the methylguanidine hydrochloride (amount of substance is unit) of 1.5 times amount and the potassium hydroxide (amount of substance is unit) of 4 times amount are dissolved in aqueous isopropanol, stirring reaction 12h at 90 DEG C, last separated purification obtains 4-(4-fluorophenyl)-6-isopropyl-N-methylpyrimidine-2-amine;
By 4-(4-fluorophenyl)-6-isopropyl-N-methylpyrimidine-2-amine (amount of substance is unit) of 1 times amount, the triethylamine (amount of substance is unit) of 5 times amount and the mesyl chloride (amount of substance is unit) of 1.2 times amount are dissolved in dichloromethane, stirring reaction 12h at 25 DEG C, last separated purification obtains 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl) amino] pyrimidine;
By 1��2.5 times amount phosphorus oxychloride (amount of substance is unit) in reaction bulb, drip the N of 1 times amount 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl) amino] pyrimidine (amount of substance is unit) and 1.1 times amount, dinethylformamide mixed solution, 108 DEG C of stirring reactions 4 hours, it is finally separating purification and obtains target compound, through structural confirmation, identical with the end-product structure of embodiment 4.
Embodiment 7
Under nitrogen protection, the sodium (amount of substance is unit) of 2.5 times amount is dissolved in isopropanol alcoholic solution, the lower ethyl isobutyrate (amount of substance is unit) to fluoro acetophenone (amount of substance is unit) and 1.2 times amount adding 1 times amount of stirring, at 45 DEG C of stirring reaction 6h, last separated purification obtains 1-(4-fluorophenyl)-4-methylpent-1,3-diketone;
By 1-(4-the fluorophenyl)-4-methylpent-1 of 1 times amount, 3-diketone (amount of substance is unit), the methylguanidine hydrochloride (amount of substance is unit) of 1.2 times amount and the potassium hydroxide (amount of substance is unit) of 3 times amount are dissolved in aqueous isopropanol, stirring reaction 12h at 80 DEG C, last separated purification obtains 4-(4-fluorophenyl)-6-isopropyl-N-methylpyrimidine-2-amine;
By 4-(4-fluorophenyl)-6-isopropyl-N-methylpyrimidine-2-amine (amount of substance is unit) of 1 times amount, the triethylamine (amount of substance is unit) of 4 times amount and the mesyl chloride (amount of substance is unit) of 1.1 times amount are dissolved in dichloromethane, stirring reaction 24h at 15 DEG C, last separated purification obtains 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl) amino] pyrimidine;
By 1��2.5 times amount phosphorus oxychloride (amount of substance is unit) in reaction bulb, drip the N of 1 times amount 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl) amino] pyrimidine (amount of substance is unit) and 1.1 times amount, dinethylformamide mixed solution, 100 DEG C of stirring reactions 5 hours, it is finally separating purification and obtains target compound, through structural confirmation, identical with embodiment 4 end-product structure.
Claims (10)
1. a synthetic method for rosuvastain calcium intermediate, described intermediate has a structure that
, it is characterised in that adopt following steps synthesis:
1) with to fluoro acetophenone and ethyl isobutyrate when sodium makes alkali, make solvent with isopropanol, prepare 1-(4-fluorophenyl through condensation reaction)-4-methylpent-1,3-diketone;
2) 1-(4-fluorophenyl)-4-methylpent-1,3-diketone; Make solvent with methylguanidine hydrochloride with isopropanol, occur ring closure reaction to obtain 4-(4-fluorophenyl)-6-isopropyl-N-methylpyrimidine-2-amine;
3) 4-(4-fluorophenyl)-6-isopropyl-N-methylpyrimidine-2-amine is with mesyl chloride with dichloromethane for solvent, generation substitution reaction obtains 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl) amino] pyrimidine;
4) 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl) amino] pyrimidine and DMF and phosphorus oxychloride occur Vilsmeier to be obtained by reacting target compound.
2. the method for claim 1, it is characterised in that: the reaction temperature of described step 1) is 30 ~ 85 DEG C.
3. the method for claim 1, it is characterised in that: described is 1:0.9 ~ 1.1:1.5 ~ 4 to fluoro acetophenone, ethyl isobutyrate and alkali mol ratio.
4. method as claimed in claim 1 or 2, it is characterised in that: described step 2) reaction temperature be 60 ~ 90 DEG C.
5. the method as described in claim 1 or 3, it is characterised in that: described 1-(4-fluorophenyl)-4-methylpent-1, the mol ratio of 3-diketone, methylguanidine hydrochloride and potassium hydroxide is 1:1 ~ 1.5:2.5 ~ 4.
6. the method as described in claim 1 or 2 or 3, it is characterised in that: the reaction temperature of described step 3) is 0 ~ 25 DEG C.
7. method as claimed in claim 1 or 2, it is characterised in that: described 4-(4-fluorophenyl)-6-isopropyl-N-methylpyrimidine-2-amine, triethylamine and mesyl chloride mol ratio be 1:3 ~ 5:1 ~ 1.2.
8. the method as described in any one of claim 1-3, it is characterised in that: the reaction temperature of described step 4) is 80 ~ 108 DEG C.
9. the method for claim 1, it is characterized in that: described 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl) amino] pyrimidine, DMF and phosphorus oxychloride mol ratio be 1:1 ~ 1.1:1 ~ 2.5; The operation of described Vilsmeier reaction is addition phosphorus oxychloride in reaction vessel, it is warming up to 90 DEG C, dropping 4-(4-fluorophenyl) mixed solution of-6-isopropyl-2-[(N-methyl-N-methylsulfonyl) amino] pyrimidine and DMF, dropwise maintenance 98 ~ 103 DEG C reaction.
10. the synthetic method of a rosuvastain calcium intermediate Formulas I, it is characterised in that: adopt following operation:
Under nitrogen protection, the sodium synthetic method of 1.5 ~ 4 times amount is dissolved in isopropanol alcoholic solution, the lower ethyl isobutyrate synthetic method to fluoro acetophenone synthetic method and 1 ~ 1.5 times amount adding 1 times amount of stirring, at 0 ~ 90 DEG C of stirring reaction 4 ~ 8h, last separated purification obtains 1-(4-fluorophenyl)-4-methylpent-1,3-diketone;
By the 1-(4-fluorophenyl of 1 times amount)-4-methylpent-1,3-diketone synthetic method, the methylguanidine hydrochloride synthetic method of 1 ~ 1.5 times amount and the potassium hydroxide synthetic method of 2.5 ~ 4 times amount are dissolved in aqueous isopropanol, stirring reaction 12h at 60 ~ 90 DEG C, last separated purification obtains 4-(4-fluorophenyl)-6-isopropyl-N-methylpyrimidine-2-amine;
By the 4-(4-fluorophenyl of 1 times amount)-6-isopropyl-N-methylpyrimidine-2-amine synthetic method, the triethylamine synthetic method of 3 ~ 5 times amount and the mesyl chloride synthetic method of 1 ~ 1.2 times amount are dissolved in dichloromethane, stirring reaction 12 ~ 36h at 0 ~ 25 DEG C, last separated purification obtains 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl) amino] pyrimidine;
By 1 ~ 2.5 times amount phosphorus oxychloride synthetic method in reaction bulb, drip 1 times amount 4-(4-fluorophenyl) N of-6-isopropyl-2-[(N-methyl-N-methylsulfonyl) amino] pyrimidine synthetic method and 1 ~ 1.1 times amount, dinethylformamide mixed solution, 98 ~ 108 DEG C of stirring reactions 4 ~ 6 hours, it is finally separating purification and obtains target compound; Described ratio is the ratio of amount of substance.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410718131.3A CN105622522B (en) | 2014-12-01 | 2014-12-01 | A kind of synthetic method of rosuvastain calcium key intermediate |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410718131.3A CN105622522B (en) | 2014-12-01 | 2014-12-01 | A kind of synthetic method of rosuvastain calcium key intermediate |
Publications (2)
Publication Number | Publication Date |
---|---|
CN105622522A true CN105622522A (en) | 2016-06-01 |
CN105622522B CN105622522B (en) | 2018-01-16 |
Family
ID=56037907
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201410718131.3A Active CN105622522B (en) | 2014-12-01 | 2014-12-01 | A kind of synthetic method of rosuvastain calcium key intermediate |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN105622522B (en) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006128954A1 (en) * | 2005-06-01 | 2006-12-07 | Fermion Oy | Process for the preparation of n-[4-(4-fluorophenyl)-5-formyl-6-isopropyl-pyrimidin-2-yl]-n-methylmethanesulfonamide |
WO2009024323A2 (en) * | 2007-08-20 | 2009-02-26 | Ratiopharm Gmbh | Process for preparing pyrimidine derivatives |
WO2010038124A1 (en) * | 2008-09-30 | 2010-04-08 | Aurobindo Pharma Limited | An improved process for preparing pyrimidine propenaldehyde |
-
2014
- 2014-12-01 CN CN201410718131.3A patent/CN105622522B/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006128954A1 (en) * | 2005-06-01 | 2006-12-07 | Fermion Oy | Process for the preparation of n-[4-(4-fluorophenyl)-5-formyl-6-isopropyl-pyrimidin-2-yl]-n-methylmethanesulfonamide |
WO2009024323A2 (en) * | 2007-08-20 | 2009-02-26 | Ratiopharm Gmbh | Process for preparing pyrimidine derivatives |
WO2010038124A1 (en) * | 2008-09-30 | 2010-04-08 | Aurobindo Pharma Limited | An improved process for preparing pyrimidine propenaldehyde |
Non-Patent Citations (1)
Title |
---|
NATALIA ANDRUSHKO,等: "A New Approach to the Total Synthesis of Rosuvastatin", 《EUROPEAN JOURNAL OF ORGANIC CHEMISTRY》 * |
Also Published As
Publication number | Publication date |
---|---|
CN105622522B (en) | 2018-01-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
SU552025A3 (en) | Method for preparing phenyl-imidazolyl alkane derivatives | |
ES2585221T3 (en) | A process for the preparation of 6- (7 - ((1-aminocyclopropyl) methoxy) -6-methoxyquinolin-4-yloxy) -n-methyl-1-naphthamide and synthetic intermediates thereof | |
EP2602250B1 (en) | Method for preparing rosuvastatin calcium intermediate | |
CN106279104B (en) | A kind of process modification method preparing amber love song Ge Lieting | |
CN101205228A (en) | Method for synthesizing phosphodiesterase 5 inhibitor tadanafil | |
CN104292122B (en) | In the production of acetoacetanilide, reduce by product 3-(phenyl amino)-2-butylene acetoacetic ester generate method | |
CN105085458B (en) | A kind of synthetic method of coumarin derivatives | |
NO861988L (en) | INTERMEDIATES FOR THE PREPARATION OF NEW SUBSTITUTED HETEROCYCLIC PHENOXYAMINES AND PROCEDURES FOR THE PREPARATION OF THEREOF. | |
CN103012260A (en) | Preparation method of pitavastatin calcium intermediate compound | |
CN105622522A (en) | Synthetic method of rosuvastatin calcium key intermediate | |
KR101725061B1 (en) | Process for preparing silodosin | |
CN111039876A (en) | Preparation method of 4-amino-2, 6-dimethoxypyrimidine | |
CN106674281B (en) | A kind of Rosuvastatin midbody compound, preparation method and its usage | |
CN105017158B (en) | A kind of preparation method of cis Rosuvastatin calcium impurities | |
CN105622521A (en) | Preparation method of rosuvastatin calcium key intermediate | |
CN114790150B (en) | 2, 3-Pyridine dicarboxylic acid ester derivative intermediate and preparation method of 2, 3-pyridine dicarboxylic acid ester derivative | |
CN110218192B (en) | Preparation method of 2-amino-4, 6-dimethoxypyrimidine | |
CN105712939B (en) | A kind of method of synthesizing rosuvastatin spit of fland calcium key intermediate | |
CN113024499A (en) | Green synthesis method of coumarin-3-carboxylic acid compounds | |
CN103044339A (en) | Preparation method of rosuvastatin calcium intermediate | |
CN104230990A (en) | 2-((4R,6S)-6-triphenylphosphoalkenylmethylene-2,2-disubstituted-1,3-dioxyhexacyclo-4-yl)acetate, and preparation method and application thereof | |
CN103755657A (en) | Preparation method of rivaroxaban intermediate | |
CN104447527A (en) | Method for preparing pyridine-2,3-dicarboxylic ester compound | |
CN104693088B (en) | A kind of preparation method of gemifloxacin side chain | |
CN102391170A (en) | Method for preparing N,N-diallyl-5-methoxytryptamine hydrochlorides |
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 | ||
CP03 | Change of name, title or address |
Address after: 400039 D1-7, Chongqing international student entrepreneurship Park, No. 71, Kecheng Road, Jiulongpo District, Chongqing Patentee after: Chongqing ruipolai Pharmaceutical Technology Co.,Ltd. Address before: 400039 D1-7, overseas student entrepreneurship Park, Kecheng Road, Jiulongpo District, Chongqing Patentee before: CHONGQING ANGE LONGXIANG PHARMACEUTICAL Co.,Ltd. |
|
CP03 | Change of name, title or address |