CN105622521B - A kind of preparation method of rosuvastain calcium key intermediate - Google Patents
A kind of preparation method of rosuvastain calcium key intermediate Download PDFInfo
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Abstract
The invention discloses the preparation method that rosuvastain calcium intermediate is compound shown in Formulas I, it comprises the following steps：A) with to fluoro acetophenone and ethyl isobutyrate reaction formula IV compounds；B) gained compound IV reacts to obtain formula III compound with methylguanidine hydrochloride and potassium hydroxide；C) compound III and triethylamine and mesyl chloride reaction formula II compounds；D) Formula II and N, N dimethylformamide and phosphorus oxychloride reaction obtain compound of formula I；Its reaction scheme is as follows：
Description
Technical field
The present invention relates to rosuvastain calcium, and in particular to the preparation method of rosuvastain calcium key intermediate.
Background technology
Rosuvastain calcium, chemical name：(3R, 5S, 6E) -7- [4- (4- fluorophenyls) -6- isopropyls -2- (N- methyl-N-
Methylsulfonyl amido) -5- pyrimidines] -3,5- dihydroxy -6- heptenoic acid calcium, be fully synthetic single enantiomter statin of new generation
Class medicine, belongs to HMG-CoA reductase inhibitor, can reduce elevated low density cholesterol, T-CHOL, triglycerides and take off
Apoprotein B concentration, while the concentration of increasing high density cholesterol, available for primary hypercholesterolemia and mixed type fat
Dysbolism disease and the complex treatment of homozygous familial hypercholesterolemia.Its structural formula is as follows：
Compound shown in Formulas I of the present invention is to prepare the important intermediate of rosuvastain calcium, European patent
EP521471 discloses a kind of synthetic method of rosuvastain calcium, wherein the preparation method of the intermediate is related to, should
The key step of technique is as follows：
The major defect of the technique is：1st, need to use DDQ (2,3- bis- chloro- 5,6- dicyanos Isosorbide-5-Nitrae benzoquinones) in technique, should
Toxicity of compound is very big；2nd, the 4- methyhnorpholine-N-oxides that are used in technique, TPAP (crossing ruthenic acid tetrapropyl ammonium) and
DIBAL-H is very expensive；3rd, DIBAL-H reduction needs to react at low temperature (- 70~-40 DEG C), power consumption, equipment and is produced into
This all can be very big, is unfavorable for industrializing sound field very much；4th, reaction yield is low.
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 a kind of simple to operate, cost
The method for preparing rosuvastain calcium intermediate Formulas I that is low, being easily achieved scale, to meet the requirement of preparation of industrialization.
The object of the present invention is achieved like this：
A kind of preparation method of rosuvastain calcium intermediate Formulas I, using following reaction scheme：
A) 1- (4- fluorophenyls) -4- is made to pass through condensation reaction in the basic conditions to fluoro acetophenone and ethyl isobutyrate
Amyl- 1, the 3- diketone (compound IV) of methyl；
B) compound IV obtains 4- (4- fluorophenyls) -6- isopropyl-N- methyl with methylguanidine hydrochloride generation ring closure reaction
Pyrimidine -2- amine (compound III)；
C) compound III obtains 4- (4- fluorophenyls) -6- isopropyls -2- [(N- first with mesyl chloride generation substitution reaction
Base-N- methylsulfonyls) amino] pyrimidine (compound II)；
D) compound II and DMF and POCl3 generation Vilsmeier react to obtain 5- (formoxyl) -4- (4- fluorobenzene
Base) -6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino] pyrimidine (compound I).
One or more combination of the alkali in sodium, sodium hydrogen, caustic alcohol.
Reaction prepare compound is carried out 0~90 DEG C in the basic conditions to fluoro acetophenone and ethyl isobutyrate in step a)
IV；Wherein the mol ratio of fluoro acetophenone, ethyl isobutyrate and alkali is preferred with 1: 0.9~1.1: 1.5~4.
Course of reaction preferably is：Under nitrogen protection, by the alkali of 1.5~4 times of amounts (amount of material is unit)
Be dissolved in alcoholic solvent, stir it is lower add 1 times of amount to fluoro acetophenone (amount of material be unit) and the isobutyric acid of 1~1.5 times of amount
Ethyl ester (amount of material is unit).In 0~90 DEG C of 4~8h of stirring reaction, most the compound of formula IV is obtained through separating-purifying afterwards.Instead
The alcoholic solvent that should be selected is methanol, ethanol, preferably isopropanol, isopropanol.
Compound IV reacts at 60~80 DEG C with methylguanidine hydrochlorate and potassium hydroxide and obtains formula III chemical combination in step b)
Thing；The mol ratio of wherein compound IV, methylguanidine hydrochloride and potassium hydroxide is preferred with 1: 1~1.5: 2.5~4.
Course of reaction preferably is：By the compound IV (amount of material is unit) of 1 times of amount, 1~1.5 times of amount
Methylguanidine hydrochloride (amount of material is unit) and 2.5~4 times amount potassium hydroxide (amount of material is unit) be dissolved in it is organic
Solvent, the stirring reaction 12h at 60~90 DEG C, most obtains the compound of formula III through separating-purifying afterwards.Reaction is selected organic molten
Agent is absolute ethyl alcohol, isopropanol, acetone, tetrahydrofuran, and preferred solvent is isopropanol.
Compound III reacts formula IIization under inert gas shielding with mesyl chloride at 0~25 DEG C in step c)
Compound；The mol ratio of wherein compound III, triethylamine and mesyl chloride is preferred with 1: 3~5: 1~1.2；
Course of reaction preferably is：By the compound III (amount of material is unit) of 1 times of amount, 3~5 times of amounts
Triethylamine (amount of material is unit) and 1~1.2 times amount mesyl chloride (amount of material is unit) be dissolved in organic solvent,
12~36h of stirring reaction at 0~25 DEG C, most obtains the compound of Formula II through separating-purifying afterwards.The reaction dissolvent is selected from dichloromethane
Alkane, chloroform, toluene, dimethylbenzene, preferably dichloromethane.
Compound II and DMF and POCl3 generation Vilsmeier react to obtain compound I in step d)；Wherein chemical combination
The mol ratio of thing II, DMF and POCl3 is preferred with 1: 1~1.1: 1~2.5.
Course of reaction preferably is：By 1~2.5 times of amount POCl3 (amount of material is unit) in reaction bulb
In, 1 times of DMF mixed solution for quantifying compound II (amount of material is unit) and 1~1.1 times of amount is added dropwise.
98~108 DEG C of stirring reactions 4~6 hours, are finally separating purification and obtain compound I.
Technique effect
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.In cyclization
During do not use the huge DDQ of toxicity, the safety of operating personnel has been effectively ensured, has met the theory of Green Chemistry.Work
The very expensive things such as 4- methyhnorpholine-N-oxides, TPAP (crossing ruthenic acid tetrapropyl ammonium), DIBAL-H are not used in skill
Material, effectively reduces production cost.Reaction condition of the present invention is gentle, and energy consumption is low, it is not necessary to special consersion unit, and operate
Simply, one pot of progress can be achieved, be easy to large-scale production.Solvent for use of the present invention can realize synchronous recovery, not only saved into
This, also protects environment.In a word, can preferably be met among industrialized mass production rosuvastain calcium using the inventive method
The requirement of body (Formulas I), there is conspicuousness industrial application value.
Embodiment
With reference to embodiment, the present invention is described in further detail and completely.
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)
Course of reaction preferably is：By 1~2.5 times of amount POCl3 (amount of material is unit) in reaction bulb
In, 1 times of DMF mixed solution for quantifying compound II (amount of material is unit) and 1~1.1 times of amount is added dropwise.
98~108 DEG C of stirring reactions 4~6 hours, are finally separating purification and obtain 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 5-7 is according to following parameter experiment, and remaining is with reference to embodiment 1-4 corresponding steps.
Compound IV made from embodiment 5-7, it is amyl- with 1- (4- fluorophenyls) -4- methyl of embodiment 1 through structural confirmation
1,3- diketone (compound IV) is identical.
Compound III made from embodiment 5-7, through structural confirmation, with 4- (4- fluorophenyls)-6- isopropyls of embodiment 2-
N- methylpyrimidine -2- amine (compound III) is identical.
Compound II made from embodiment 5-7, through structural confirmation, with 4- (4- fluorophenyls)-6- isopropyls of embodiment 3-
2- [(N- methyl-N- methylsulfonyls) amino] pyrimidine (compound II) is identical.
Compound I made from embodiment 5-7, through structural confirmation, with 5- (formoxyl)-4- (4- fluorophenyls) of embodiment 4-
6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino] pyrimidine (compound I) is identical.
Finally be necessary described herein be：Above example is 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.
Claims (6)
1. a kind of preparation method of rosuvastain calcium intermediate Formulas I, it is characterised in that comprise the following steps：
Its reaction scheme is as follows：
A) 1- is made to pass through condensation reaction in the presence of alkali to fluoro acetophenone and ethyl isobutyrate（4- fluorophenyls）- 4- first
Amyl- 1, the 3- diketone of base, i.e. compound IV；
B) the generation ring closure reaction under potassium hydroxide effect obtains 4- to compound IV with methylguanidine hydrochloride（4- fluorophenyls）-6-
Isopropyl-N- methylpyrimidine -2- amine, i.e. compound III；
C) the generation substitution reaction under triethylamine effect obtains 4- to compound III with mesyl chloride（4- fluorophenyls）- 6- isopropyls-
2- [(N- methyl-N- methylsulfonyls) amino] pyrimidine, i.e. compound II；
D) compound ii reacts to obtain 5- (formoxyl) -4- with DMF and POCl3 generation Vilsmeier（4- fluorophenyls）-6-
Isopropyl -2- [（N- methyl-N- methylsulfonyls）Amino] pyrimidine, i.e. compound I；
Wherein, step d) compound II, DMF and POCl3 mol ratio are 1:1~1.1:1~2.5；Institute
The operation of Vilsmeier reactions is stated to add POCl3 into reaction vessel, 90 DEG C is warming up to, compound II and DMF is added dropwise
Mixed solution, 98 ~ 103 DEG C of holding reaction is added dropwise.
2. the method as described in claim 1, it is characterised in that：The one kind or several of the alkali in sodium hydride, sodium, caustic alcohol
Kind combination.
3. method as claimed in claim 1 or 2, it is characterised in that：It is described to fluoro acetophenone, ethyl isobutyrate and alkali mol ratio
For 1:0.9~1.1:1.5~4；It is described that reaction preparationization is carried out 0 ~ 90 DEG C in the basic conditions to fluoro acetophenone and ethyl isobutyrate
Compound IV.
4. method as claimed in claim 1 or 2, it is characterised in that：Compound IV, methylguanidine hydrochloride and potassium hydroxide rub
You are than being 1：1~1.5：2.5~4；The compound IV reacts at 60 ~ 90 DEG C with methylguanidine hydrochlorate and potassium hydroxide and obtains formula III
Compound.
5. method as claimed in claim 1 or 2, it is characterised in that：Mole of the compound III, triethylamine and mesyl chloride
Than for 1:3~5:1~1.2；Compound III reacts the chemical combination of formula II under inert gas shielding with mesyl chloride at 0 ~ 25 DEG C
Thing.
6. method as claimed in claim 5, it is characterised in that：The inert gas is nitrogen.
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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 |
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2014
- 2014-12-01 CN CN201410718049.0A patent/CN105622521B/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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