CN105622522B - A kind of synthetic method of rosuvastain calcium key intermediate - Google Patents
A kind of synthetic method of rosuvastain calcium key intermediate Download PDFInfo
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- CN105622522B CN105622522B CN201410718131.3A CN201410718131A CN105622522B CN 105622522 B CN105622522 B CN 105622522B CN 201410718131 A CN201410718131 A CN 201410718131A CN 105622522 B CN105622522 B CN 105622522B
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- SGKWXUFSWOFKOS-UHFFFAOYSA-N CC(C)c1c(CO)c(-c(cc2)ccc2F)nc(N(C)S(C)(O)O)n1 Chemical compound CC(C)c1c(CO)c(-c(cc2)ccc2F)nc(N(C)S(C)(O)O)n1 SGKWXUFSWOFKOS-UHFFFAOYSA-N 0.000 description 1
- QPYJJPKQNCMTDO-UHFFFAOYSA-N CC(C)c1cc(-c(cc2)ccc2F)nc(N(C)S(C)(=O)=O)n1 Chemical compound CC(C)c1cc(-c(cc2)ccc2F)nc(N(C)S(C)(=O)=O)n1 QPYJJPKQNCMTDO-UHFFFAOYSA-N 0.000 description 1
- OGLVCICEABIJKL-UHFFFAOYSA-N CC(C)c1cc(-c(cc2)ccc2F)nc(NC)n1 Chemical compound CC(C)c1cc(-c(cc2)ccc2F)nc(NC)n1 OGLVCICEABIJKL-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses a kind of synthetic method of rosuvastain calcium intermediate Formulas I；It is specific as follows：Under conditions of sodium makees alkali, to make solvent to fluoro acetophenone and ethyl isobutyrate with isopropanol, 1 be made by condensation reaction（4 fluorophenyls）The diketone of 4 methylpent 1,3；Solvent is made with isopropanol with methylguanidine hydrochloride again, ring closure reaction occurs and obtains 4（4 fluorophenyls）The amine of 6 isopropyl N methylpyrimidines 2；Again with mesyl chloride using dichloromethane as solvent, substitution reaction occurs and obtains 4（4 fluorophenyls）6 isopropyl 2 [(N methyl Ns methylsulfonyl) amino] pyrimidines；Vilsmeier finally occurs with DMF and POCl3 to react to obtain target compound.The inventive method has the advantages that gentle simple to operate, raw materials used cheap and easy to get, reaction condition, equipment requirement, production cost is low, is easy to large-scale production, has conspicuousness industrial application value.
Description
Technical field
The present invention relates to rosuvastain calcium, and in particular to the synthetic method of rosuvastain calcium key intermediate.
Background technology
Rosuvastain calcium, it is the statins of new generation of fully synthetic single enantiomter, can reduces elevated low
Density cholesterol, T-CHOL, triglycerides and apoB concentration, while the concentration of increasing high density cholesterol, can be used
In the complex treatment of primary hypercholesterolemia and mixed type dyslipidemia and homozygous familial hypercholesterolemia,
Belong to HMG-CoA reductase inhibitor.
5- (formoxyl) -4- (4- fluorophenyls) -6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino] pyrimidine is synthesis
One important intermediate of rosuvastain calcium, its structural formula are following (Formulas I)：
European patent EP 521471 discloses a kind of synthetic method of rosuvastain calcium, wherein relating to the centre
The preparation method of body, the key step of the technique are as follows：
The technique has used the huge DDQ of toxicity (2,3- bis- chloro- 5,6- dicyanos Isosorbide-5-Nitrae benzoquinones), is unfavorable for operating personnel
Health, do not meet the idea of development of Green Chemistry；In addition, the process recovery ratio is low, it is unfavorable for large-scale production.
The content of the invention
In view of the above-mentioned problems existing in the prior art and defect, it is an object of the invention to provide in a kind of rosuvastain calcium
The synthetic method of mesosome Formulas I, this method endanger operator's health low, 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,
The intermediate has following structure：
Synthesized using following steps：
1) it is anti-by being condensed under conditions of sodium makees alkali, to make solvent with isopropanol to fluoro acetophenone and ethyl isobutyrate
Amyl- 1, the 3- diketone of 1- (4- fluorophenyls) -4- methyl should be made；
2) amyl- 1, the 3- diketone of 1- (4- fluorophenyls) -4- methyl makees solvent with methylguanidine hydrochloride with isopropanol, and cyclization occurs
Reaction obtains 4- (4- fluorophenyls) -6- isopropyl-N- methylpyrimidine -2- amine；
3) 4- (4- fluorophenyls) -6- isopropyl-N- methylpyrimidine -2- amine is sent out with mesyl chloride using dichloromethane as solvent
Raw substitution reaction obtains 4- (4- fluorophenyls) -6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino] pyrimidine；
4) 4- (4- fluorophenyls) -6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino] pyrimidines and DMF and POCl3
Generation Vilsmeier reacts to obtain target compound.
The reaction temperature of the step 1) is preferred with 30~85 DEG C, wherein to fluoro acetophenone, ethyl isobutyrate and sodium hydride
Mol ratio be preferred with 1: 0.9~1.1: 1.5~4.
The reaction temperature of the step 2) is preferred for 60~90 DEG C, amyl- 1, the 3- bis- of wherein 1- (4- fluorophenyls) -4- methyl
The mol ratio of ketone, methylguanidine hydrochloride and potassium hydroxide is 1: 1~1.5: 2.5~4.
The reaction temperature of the step 3) is 0~25 DEG C, wherein 4- (4- fluorophenyls) -6- isopropyl-N- methylpyrimidines -2-
The mol ratio of amine, triethylamine and mesyl chloride is 1: 3~5: 1~1.2.
The reaction temperature of the step 4) is 80~108 DEG C；Wherein 4- (4- fluorophenyls) -6- isopropyls -2- [(N- methyl -
N- methylsulfonyls) amino] pyrimidine, DMF and POCl3 mol ratio be 1: 1~1.1: 1~2.5.
The operation of the Vilsmeier reactions is warming up to 90 DEG C, 4- is added dropwise to add POCl3 into reaction vessel
The mixed solution of (4- fluorophenyls) -6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino] pyrimidines and DMF, is added dropwise holding
98~103 DEG C of reactions.
A kind of synthetic method of rosuvastain calcium intermediate Formulas I, it is characterised in that：Using following operation：
Under nitrogen protection, the sodium (amount of material is unit) of 1.5~4 times of amounts is dissolved in isopropanol alcoholic solution, under stirring
Adding 1 times of ethyl isobutyrate measured to fluoro acetophenone (amount of material is unit) and 1~1.5 times measured, (amount of material is single
Position), in 0~90 DEG C of 4~8h of stirring reaction, most obtain amyl- 1, the 3- diketone of 1- (4- fluorophenyls) -4- methyl through separating-purifying afterwards；
By 1 times amount amyl- 1, the 3- diketone of 1- (4- fluorophenyls) -4- methyl (amount of material be unit), 1~1.5 times measure
Methylguanidine hydrochloride (amount of material is unit) and the potassium hydroxide (amount of material is unit) of 2.5~4 times of amounts are dissolved in isopropanol
In solution, the stirring reaction 12h at 60~90 DEG C, most 4- (4- fluorophenyls) -6- isopropyl-N- methyl is obtained through separating-purifying afterwards
Pyrimidine -2- amine；
4- (4- fluorophenyls) -6- isopropyl-N- methylpyrimidine -2- amine (amount of material is unit) that 1 times is measured, 3~5 times
The triethylamine (amount of material is unit) of amount and the mesyl chloride (amount of material is unit) of 1~1.2 times of amount are dissolved in dichloromethane
In, 12~36h of stirring reaction at 0~25 DEG C, most obtain 4- (4- fluorophenyls) -6- isopropyl -2- [(N- through separating-purifying afterwards
Methyl-N- methylsulfonyls) amino] pyrimidine；
By 1~2.5 times of amount POCl3 (amount of material is unit) in reaction bulb, 1 times of amount 4- (4- fluorophenyls) of dropwise addition-
The N of 6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino] pyrimidines (amount of material is unit) and 1~1.1 times of amount, N- diformazans
Base formamide mixed solution, in 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 is so as to fluoro acetophenone and ethyl isobutyrate, as initiation material, raw material sources are extensive, cheap and easy to get.Closing
The huge DDQ of toxicity is not used during ring, the safety of operating personnel has been effectively ensured, meets the theory of Green Chemistry.
2. do not use 4- methylmorpholine N-oxides, TPAP (crossing ruthenic acid tetrapropyl ammonium), DIBAL-H etc. non-in technique
Chang Anggui material, effectively reduces production cost.
3. reaction condition of the present invention is gentle, energy consumption is low, it is not necessary to special consersion unit, and also it is simple to operate, it can be achieved
One pot of progress, is easy to large-scale production.
4. solvent for use of the present invention can realize synchronous recovery, cost is not only saved, has also protected environment.
In a word, industrialized mass production rosuvastain calcium intermediate (Formulas I) can preferably be met using the inventive method
Requirement, there is conspicuousness industrial application value.
Embodiment
Finally be necessary described herein be：Following examples are served only for further detailed to technical scheme work
Explanation, it is impossible to be interpreted as limiting the scope of the invention, those skilled in the art do not depart from the spirit of the present invention and
In the case of scope, should various modifications may be made with change.Therefore protection scope of the present invention should be considered as appended power
Sharp claim limited range.
Embodiment 1：The synthesis of amyl- 1, the 3- diketone (compound IV) of 1- (4- fluorophenyls) -4- methyl
150g isopropanols are added into 0.5L three-necked flask, after be added portionwise 6.9g sodium, the dissolving of strong agitation sodium is complete
Afterwards, it is added dropwise and the molten of 80g isopropanols is dissolved in fluorine-based acetophenone 13.81g (0.1mol) and ethyl isobutyrate 11.62g (0.1mol)
Liquid.Reaction solution is cooled to room temperature, is stirred overnight in 82 DEG C of back flow reaction 6h.Large-tonnage product separate out, filter off-white color into
Product, 40 DEG C of convection ovens are dried to constant weight, obtain 18g, yield 86%.Nuclear magnetic data (1HNMR, 500MHz, internal standard TMS, solvent
CDCl3 it 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).
Embodiment 2：The synthesis of 4- (4- fluorophenyls) -6- isopropyl-N- methylpyrimidine -2- amine (compound III)
10.4g (0.05mol) compound IV, 6g (0.055mol) methylguanidine hydrochloric acid is added into 250ml three-necked flask
Salt, 8.4g (0.15mol) potassium hydroxide, 100ml isopropanols, temperature rising reflux reaction is overnight.Reaction terminates, and it is different to be evaporated under reduced pressure removing
Propyl alcohol, 10 DEG C are naturally cooled to, filtering, a small amount of isopropanol elutes 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, internal standard 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).
Embodiment 3：4- (4- fluorophenyls) -6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino] pyrimidine (compound II)
Synthesis
Under nitrogen protection, 9.8g (0.04mol) compound III and 100ml dichloromethane is added into 250ml three-necked flask
Alkane, it is cooled to 5 DEG C., add 12.1g (0.12mol) triethylamine, stirring reaction half an hour.5.5g is slowly added dropwise into reaction solution
(0.048mol) mesyl chloride is dissolved in the solution of 5ml dichloromethane, continues stirring reaction 12h in 0~25 DEG C.Reaction terminates, and adds
Enter 20ml dichloromethane, 30ml purifying, concentrated hydrochloric acid adjusts pH=2~3, and layering obtains organic layer.Gained organic layer 50ml saturations
Brine It once, 10g anhydrous sodium sulfate dryings, filters.Depressurize precipitation and remove dichloromethane, 50ml is added into residue
Methanol, stirring are cooled to 5 DEG C, filter, and dry, obtain 11g white solid II, yield 85%.Nuclear magnetic data (1HNMR, 500MHz,
Internal standard TMS, solvent DMSO) it 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).
Embodiment 4：5- (formoxyl) -4- (4- fluorophenyls) -6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino] is phonetic
The synthesis of pyridine (compound I)
9.2g (0.06mol) POCl3 is added into 100ml three-necked flask, stirring is opened and is warming up to 90 DEG C, be added dropwise
9.7g (0.03mol) compound II and 2.4g (0.033mol) DMF mixed solution, continues after being added dropwise
98~108 DEG C of controlling reaction temperature is reacted about 4~6 hours.Reaction terminate after, be cooled to room temperature, by system drop add to
In 50ml water, a large amount of solids are added dropwise and separate out, filtering, filter cake is washed with water to weakly acidic pH.Gained filter cake adds 20ml acetic acid second
Ester recrystallizes, and filters, and dries, obtains 7.6g white solid I, yield 72%.Nuclear magnetic data (1HNMR, 500MHz, internal standard TMS are molten
Agent CDCl3) 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 material is unit) of 1.5 times of amounts is dissolved in isopropanol alcoholic solution, stirs lower add
1 times amount to fluoro acetophenone (amount of material be unit) and 1 times amount ethyl isobutyrate (amount of material is unit), stirred at 0 DEG C
Reaction 8h is mixed, most obtains amyl- 1, the 3- diketone of 1- (4- fluorophenyls) -4- methyl through separating-purifying afterwards；
By amyl- 1, the 3- diketone of 1- (4- fluorophenyls) -4- methyl (amount of material is unit) of 1 times of amount, the methylguanidine of 1 times of amount
Hydrochloride (amount of material is unit) and the potassium hydroxide (amount of material is unit) of 2.5 times of amounts are dissolved in aqueous isopropanol,
Stirring reaction 12h at 60 DEG C, most obtain 4- (4- fluorophenyls) -6- isopropyl-N- methylpyrimidine -2- amine through separating-purifying afterwards；
By 4- (4- fluorophenyls) -6- isopropyl-N- methylpyrimidine -2- amine (amount of material is unit) of 1 times of amount, 3 times of amounts
Triethylamine (amount of material is unit) and 1 times amount mesyl chloride (amount of material is unit) be dissolved in dichloromethane, at 0 DEG C
Lower stirring reaction 36h, most obtain 4- (4- fluorophenyls) -6- isopropyls -2- [(N- methyl-N- methylsulfonyls) ammonia through separating-purifying afterwards
Base] pyrimidine；
By 1~2.5 times of amount POCl3 (amount of material is unit) in reaction bulb, 1 times of amount 4- (4- fluorophenyls) of dropwise addition-
The N of 6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino] pyrimidines (amount of material is unit) and 1 times of amount, N- dimethyl formyls
Amine mixed solution, in 98 DEG C of stirring reactions 6 hours, it is finally separating purification and obtains target compound.Structural confirmation, gained targeted
Compound is identical with the end-product structure of embodiment 4.
Embodiment 6
Under nitrogen protection, the sodium (amount of material is unit) of 4 times of amounts is dissolved in isopropanol alcoholic solution, stirs lower addition 1
Times amount to fluoro acetophenone (amount of material be unit) and 1~1.5 times amount ethyl isobutyrate (amount of material is unit), 90
DEG C stirring reaction 4h, most obtains amyl- 1, the 3- diketone of 1- (4- fluorophenyls) -4- methyl through separating-purifying afterwards；
By amyl- 1, the 3- diketone of 1- (4- fluorophenyls) -4- methyl (amount of material is unit) of 1 times of amount, the methyl of 1.5 times of amounts
Guanidine hydrochloride (amount of material is unit) and the potassium hydroxide (amount of material is unit) of 4 times of amounts are dissolved in aqueous isopropanol,
Stirring reaction 12h at 90 DEG C, most obtain 4- (4- fluorophenyls) -6- isopropyl-N- methylpyrimidine -2- amine through separating-purifying afterwards；
By 4- (4- fluorophenyls) -6- isopropyl-N- methylpyrimidine -2- amine (amount of material is unit) of 1 times of amount, 5 times of amounts
Triethylamine (amount of material is unit) and 1.2 times amount mesyl chlorides (amount of material is unit) be dissolved in dichloromethane,
Stirring reaction 12h at 25 DEG C, most obtain 4- (4- fluorophenyls) -6- isopropyls -2- [(N- methyl-N- first sulphurs through separating-purifying afterwards
Acyl) amino] pyrimidine；
By 1~2.5 times of amount POCl3 (amount of material is unit) in reaction bulb, 1 times of amount 4- (4- fluorophenyls) of dropwise addition-
The N of 6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino] pyrimidines (amount of material is unit) and 1.1 times of amounts, N- dimethyl methyls
Acid amides mixed solution, in 108 DEG C of stirring reactions 4 hours, it is finally separating purification and obtains target compound, through structural confirmation, with reality
The end-product structure for applying example 4 is identical.
Embodiment 7
Under nitrogen protection, the sodium (amount of material is unit) of 2.5 times of amounts is dissolved in isopropanol alcoholic solution, stirs lower add
1 times amount to fluoro acetophenone (amount of material be unit) and 1.2 times amounts ethyl isobutyrates (amount of material is unit), at 45 DEG C
Stirring reaction 6h, most obtain amyl- 1, the 3- diketone of 1- (4- fluorophenyls) -4- methyl through separating-purifying afterwards；
By amyl- 1, the 3- diketone of 1- (4- fluorophenyls) -4- methyl (amount of material is unit) of 1 times of amount, the methyl of 1.2 times of amounts
Guanidine hydrochloride (amount of material is unit) and the potassium hydroxide (amount of material is unit) of 3 times of amounts are dissolved in aqueous isopropanol,
Stirring reaction 12h at 80 DEG C, most obtain 4- (4- fluorophenyls) -6- isopropyl-N- methylpyrimidine -2- amine through separating-purifying afterwards；
By 4- (4- fluorophenyls) -6- isopropyl-N- methylpyrimidine -2- amine (amount of material is unit) of 1 times of amount, 4 times of amounts
Triethylamine (amount of material is unit) and 1.1 times amount mesyl chlorides (amount of material is unit) be dissolved in dichloromethane,
Stirring reaction 24h at 15 DEG C, most obtain 4- (4- fluorophenyls) -6- isopropyls -2- [(N- methyl-N- first sulphurs through separating-purifying afterwards
Acyl) amino] pyrimidine；
By 1~2.5 times of amount POCl3 (amount of material is unit) in reaction bulb, 1 times of amount 4- (4- fluorophenyls) of dropwise addition-
The N of 6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino] pyrimidines (amount of material is unit) and 1.1 times of amounts, N- dimethyl methyls
Acid amides mixed solution, in 100 DEG C of stirring reactions 5 hours, it is finally separating purification and obtains target compound, through structural confirmation, with reality
It is identical to apply the end-product structure of example 4.
Claims (6)
1. a kind of synthetic method of rosuvastain calcium intermediate, the intermediate have following structure：
, it is characterised in that synthesized using following steps：
1）Under conditions of sodium makees alkali, to make solvent with isopropanol, by condensation reaction system to fluoro acetophenone and ethyl isobutyrate
Obtain 1-（4- fluorophenyls）The amyl- 1,3- diketone of -4- methyl；
2)1-（4- fluorophenyls）Amyl- 1, the 3- diketone of -4- methyl makees solvent with methylguanidine hydrochloride with isopropanol, and ring closure reaction occurs
Obtain 4-（4- fluorophenyls）- 6- isopropyl-N- methylpyrimidine -2- amine；
3)4-（4- fluorophenyls）- 6- isopropyl-N- methylpyrimidine -2- amine, using dichloromethane as solvent, takes with mesyl chloride
Generation reaction obtains 4-（4- fluorophenyls）- 6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino] pyrimidine；
4)4-（4- fluorophenyls）- 6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino] pyrimidines occur with DMF and POCl3
Vilsmeier reacts to obtain target compound；
The 4-（4- fluorophenyls）- 6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino] pyrimidine, DMF and POCl3 rub
You are than being 1：1~1.1：1~2.5；The operation of the Vilsmeier reactions is warming up to add POCl3 into reaction vessel
90 DEG C, 4- is added dropwise（4- fluorophenyls）The mixed solution of -6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino] pyrimidines and DMF,
98 ~ 103 DEG C of reactions of holding are added dropwise.
2. the method as described in claim 1, it is characterised in that：The step 1）Reaction temperature be 30 ~ 85 DEG C.
3. the method as described in claim 1, it is characterised in that：It is described to be to fluoro acetophenone, ethyl isobutyrate and alkali mol ratio
1：0.9~1.1：1.5~4.
4. method as claimed in claim 1 or 2, it is characterised in that：The step 2）Reaction temperature be 60 ~ 90 DEG C.
5. the method as described in claim 1 or 2 or 3, it is characterised in that：The step 3）Reaction temperature be 0 ~ 25 DEG C.
6. a kind of synthetic method of rosuvastain calcium intermediate Formulas I, the intermediate have following structure：
, it is characterised in that synthesized using following steps：
Under nitrogen protection, the sodium of 1.5 ~ 4 times of amounts are dissolved in isopropanol alcoholic solution, stir it is lower add 1 times of amount to fluoro acetophenone
With the ethyl isobutyrate of 1 ~ 1.5 times of amount, in 0 ~ 90 DEG C of 4 ~ 8h of stirring reaction, most 1- is obtained through separating-purifying afterwards（4- fluorophenyls）-
The amyl- 1,3- diketone of 4- methyl；
By the 1- of 1 times of amount（4- fluorophenyls）Amyl- 1, the 3- diketone of -4- methyl, 1 ~ 1.5 times amount methylguanidine hydrochloride and 2.5 ~ 4 times
The potassium hydroxide of amount is dissolved in aqueous isopropanol, and stirring reaction 12h, most obtains 4- through separating-purifying afterwards at 60 ~ 90 DEG C（4- fluorine
Phenyl）- 6- isopropyl-N- methylpyrimidine -2- amine；
By the 4- of 1 times of amount（4- fluorophenyls）- 6- isopropyl-N- methylpyrimidine -2- amine, the triethylamine and 1 ~ 1.2 times of amount of 3 ~ 5 times of amounts
Mesyl chloride be dissolved in dichloromethane, 12 ~ 36h of stirring reaction, most obtains 4- through separating-purifying afterwards at 0 ~ 25 DEG C（4- fluorobenzene
Base）- 6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino] pyrimidine；
By 1 ~ 2.5 times of amount POCl3 in reaction bulb, 1 times of amount 4- is added dropwise（4- fluorophenyls）- 6- isopropyls -2- [(N- methyl -
N- methylsulfonyls) amino] pyrimidine and 1 ~ 1.1 times amount DMF mixed solution, in 98 ~ 108 DEG C of stirring reactions 4 ~ 6
Hour, it is finally separating purification and obtains target compound；The ratio is the ratio between amount of material.
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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 |
|---|
| A New Approach to the Total Synthesis of Rosuvastatin;Natalia Andrushko，等;《European Journal of Organic Chemistry》;20071112;第2008卷(第5期);第847-853页 * |
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