CN107235918A - The preparation method of rosuvastain calcium intermediate - Google Patents
The preparation method of rosuvastain calcium intermediate Download PDFInfo
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- CN107235918A CN107235918A CN201710520711.5A CN201710520711A CN107235918A CN 107235918 A CN107235918 A CN 107235918A CN 201710520711 A CN201710520711 A CN 201710520711A CN 107235918 A CN107235918 A CN 107235918A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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Abstract
The invention provides the preparation method of rosuvastain calcium intermediate.Rosuvastain calcium intermediate is the preparation method of compound shown in formula I, whereinFor formula I, comprise the following steps：（1）By the compound 5 of 4-Fluorobenzaldehyde, methyl isobutyrylacetate, urea in the presence of the catalyst shown in production II, wherein Formula II is；（2）By compound 6 of the compound 5 in the presence of the oxidant potassium peroxydisulfate shown in production III, wherein formula III is；（3）By compound 6, paratoluensulfonyl chloride, N methylmethanesulfonamides in the presence of catalyst compound 7 shown in production IV, wherein formula IV is
Description
Technical field
Field is synthesized the present invention relates to medicine, and in particular to the preparation method of rosuvastain calcium intermediate.
Background technology
With rosuvastain calcium (Rosuvastatin Calcium), chemical name：Double-[E-7- [4- (the fluorine-based phenyl of 4-)-
6- isopropyls -2- [methyl (mesyl) amino]-pyrimidine -5- bases]-(3R, 5S) -3,5- dihydroxy heptyl -6- olefin(e) acids] calcium salt,
It is a kind of statins antilipemic drugs, belongs to HMG CoA (HMG-CoA) reductase inhibitor.Rosuvastatin
Calcium is Japanese Shionogi city.This product can significantly raise HDL-C, with other statins listed while LDC-C is reduced
Class medicine is compared, and rosuvastain calcium has more preferable pharmacological characteristics in terms of the inhibitory action of HMG-COA reductases, simultaneously
Possess the low advantage of toxic side effect, be described as " superstatin ".
For the synthesis of rosuvastain calcium, its important intermediate 4- (4- fluorophenyls) -6- isopropyls -2- [(N- methyl-N- first
Sulphonyl) amino] synthesis of pyrimidine -5- methanol (compound 1) is the focus of current technical study.
The document report for having related compounds 1 to synthesize is more, mainly there is two synthetic routes：
(1) synthetic route I is
(2) synthetic route II is
Synthetic route II is improved on the basis of synthetic route I, simple to operate compared to former route, and step shortens, yield
Improve, but still there is problems with：
(1) by the use of a large amount of nitric acid being oxidant during compound 5 aoxidizes prepare compound 6, environmental pollution is big, rear place
Reason needs a large amount of alkali lye to neutralize, and production efficiency is low；
(2) reduced by compound 7 during obtaining target compound 1, mainly there are two methods, first method is will first to change
Compound 7 is hydrolyzed to acid, reuses potassium borohydride reduction for alcohol, this method increases synthesis step and production cost.Second of side
Method needs to be reduced directly compound 7 with diisobutyl aluminium hydride (DIBAL-H) under -78 DEG C of low temperature, and the method reaction condition is severe
Carve, be not suitable for industrialized production.Therefore as the important intermediate of rosuvastain calcium, the synthesis technique of compound 1 has huge
Big Improvement requirement and space.
The content of the invention
The technical problem to be solved：It is an object of the invention to provide the preparation method of rosuvastain calcium intermediate, it is given birth to
Produce that cost is low, it is mild condition, easy to operate.
Technical scheme：Rosuvastain calcium intermediate is the preparation method of compound 1 shown in formula I,
It is characterised in that it includes following steps：
(1) compound by 4-Fluorobenzaldehyde, methyl isobutyrylacetate and urea in the presence of the catalyst shown in production II
5；
(2) compound 6 by compound 5 in the presence of the oxidant potassium peroxydisulfate shown in production III；
(3) by compound 6, paratoluensulfonyl chloride and N- methylmethanesulfonamides in the presence of catalyst chemical combination shown in production IV
Thing 7；
(4) target compound 1 by compound 7 in the presence of the reducing agent red aluminum solution shown in normal-temperature reaction production I, then will
Target compound 1 is crystallized with crystallization solution, the target compound 1 purified；
Specifically synthetic route is：
Further, the preparation method of described rosuvastain calcium intermediate, catalyst described in step (1) is methanol,
The mixture of stannous chloride and sulfuric acid.
Further, the preparation method of described rosuvastain calcium intermediate, the catalyst described in step (3) is potassium carbonate
Or the mixture of potassium carbonate and n-butyl acetate.
Further, the preparation method of described rosuvastain calcium intermediate, the crystallization solution described in step (4) is acetic acid
The mixed solution of ethyl ester and normal heptane.
Further, the preparation method of described rosuvastain calcium intermediate, described ethyl acetate and the volume of normal heptane
Than for 1:2.
Beneficial effect：The present invention provides the preparation method of rosuvastain calcium intermediate, compared with prior art, and the present invention is main
With advantages below：
(1) using potassium peroxydisulfate as oxidant, react more clean, post processing is simple, and avoid and largely used in former technique
The harmful effect that nitric acid is produced；
(2) using red aluminum solution as reducing agent, reacted at 0 DEG C, its reaction condition is gentle, and high conversion rate, impurity is less, overcomes
Using diisobutyl aluminium hydride as reducing agent, the problem of reaction cost is high at -30 DEG C；
(3) production obtains compound 1 without crystallization at present, is directly rotated to dry and obtained by extract, it is difficult to ensure that final production
The quality of product, and the demand of industrialized production is not suitable with, the present invention is from ethyl acetate/normal heptane solvent system crystallization production
Product, it is ensured that the balance of product yield and quality.
Embodiment
Embodiment 1
The preparation of 1.1 Formula II compounds 5
Methanol, 4-Fluorobenzaldehyde 24.8g (0.2mol), methyl isobutyrylacetate 28.8g are added in 1000mL three-neck flasks
(0.2mol), urea 21g (0.35mol), stannous chloride 0.2g (0.002mol) and 1mol/L sulfuric acid 2mL, are heated to 78 DEG C and return
Stream reaction 9h, the lower 0 DEG C of stirring 2h of ice-water bath, filtering washes 3 times with cold ethanol, 65 DEG C of dry 55.3g compounds 5, yield
94.5%, mp:224~225 DEG C.1H-NMR(CDCl3,400MHz)δ:1.18~1.23 (d, 6H, CH3×2),3.62(s,3H,
CH3), 4.13~4.16 (m, 1H, CHCH3CH3),5.30(d,1H,CHNH),5.54(d,1H,CHNH), 6.86(s,1H,
), NH 6.99~7.02 (m, 2H, ArH), 7.26~7.29 (m, 2H, ArH).
The synthesis of 1.2 formula III compounds 6
Compound 5 is sequentially added into 500mL three-necked bottles for 55g (0.19mol), potassium peroxydisulfate 50.8g (0.19mol), acetonitrile
300ml, water 60ml are heated to backflow, stir 5h.After reaction completely, decompression steams acetonitrile, adds water 300ml, uses concentrated hydrochloric acid
PH value is adjusted to 1-2, ethyl acetate 300ml extractions is added, discards organic phase, aqueous phase is neutralized to 5mol/L sodium hydroxide solutions
Neutrality, separates out a large amount of yellow solids, stirs 30min, suction filtration, washing, dry 51.73g compounds 6, yield 95.0%. mp:
192~193 DEG C.1H-NMR(CDCl3,400MHz)δ:1.27~1.42 (d, 6H, CH3× 2), 3.23~3.26 (m, 1H,
CHCH3CH3),3.61(s,3H,CH3), 7.14~7.18 (m, 2H, ArH), 7.60~7.65 (m, 2H, ArH),
13.03(s,1H,OH)。
The synthesis of 1.3 formula IV compounds 7
51g (0.18mol) compound 6, potassium carbonate powder 31.9g (0.23mol), the positive fourth of acetic acid are added in 1000mL round-bottomed flasks
Ester 340mL, paratoluensulfonyl chloride 38g (0.2mol), are warming up to 45 DEG C, stirring 30min reactions are complete, add potassium carbonate powder
37.3g (0.27mol), N- methylmethanesulfonamides 25.1g (0.23mol) are warming up to 125 DEG C of back flow reactions, stir 3h, are cooled to
Room temperature, reaction solution is poured into 400mL water, stirs 10min, and point liquid, water layer is extracted 3 times with n-butyl acetate, merges organic layer, is used
Washing 2 times, saturated common salt is washed 2 times, and organic phase anhydrous Na 2SO4 is dried, and is concentrated to give crude white solid 69g, is used 95% second
Alcohol is recrystallized, 65 DEG C of dry 64.6g white solids, as compound 7, yield 94.0%, mp:128~130 DEG C.1H-NMR
(CDCl3,400MHz)δ:1.31~1.33 (d, 6H, CH3× 2), 3.20~3.23 (m, 1H, CHCH3CH3), 3.55(s,3H,
CH3),3.61(s,3H,NCH3), 3.70 (s, 3H, SCH3), 7.14~7.18 (m, 2H, ArH), 7.67~7.70 (m, 2H,
ArH)。
1.4 Formulas I target compound I preparation
Tetrahydrofuran 600ml is sequentially added into 1000mL three-necked bottles, compound 7 is 69g (0.18mol), under ice bath stirring, drop
The red aluminum toluene solution 130.68g (0.45mol) for plus 70%, after reaction completely, adds water 500ml, layering, organic phase is distinguished again
With 10%Na2CO3 solution and saturated common salt water washing, be concentrated under reduced pressure organic phase, obtains crude product, then with ethyl acetate/normal heptane
(v/v1/2) it is recrystallized to give white solid 60.2g, yield 94.2%, mp:134℃.Target compound I total recovery is
79.5%.1H-NMR(CDCl3,400MHZ)δ:1.32~1.34 (d, 6H, CH3×2), 3.48(m,1H,CHCH3CH3),3.51
(s,3H,NCH3),3.52(s,3H,SCH3), 4.64 (s, 2H, CH2OH), 7.16~7.19 (m, 2H, ArH), 7.67~7.71
(m,2H,ArH)。
Comparative example 1
The preparation of 2.1 Formula II compounds 5
Methanol, 4-Fluorobenzaldehyde 49.6g (0.4mol), methyl isobutyrylacetate 57.6g are added in 1000mL three-neck flasks
(0.4mol), urea 42g (0.7mol), stannous chloride 0.4g (0.004mol) and 1mol/L sulfuric acid 4mL, are heated to 78 DEG C of backflows
9h is reacted, the lower 0 DEG C of stirring 2h of ice-water bath, filtering washes 3 times with cold ethanol, 65 DEG C of dry 110.6g compounds 5, yield
94.5%, mp:224~225 DEG C.1H-NMR(CDCl3,400MHz)δ:1.18~1.23 (d, 6H, CH3×2),3.62(s,3H,
CH3), 4.13~4.16 (m, 1H, CHCH3CH3),5.30(d,1H,CHNH),5.54(d,1H,CHNH), 6.86(s,1H,
), NH 6.99~7.02 (m, 2H, ArH), 7.26~7.29 (m, 2H, ArH).
The synthesis of 2.2 Formula II compounds 6
In 1000mL three-necked flasks, add under 61.2g (0.209mol) compound 5, mechanical agitation and 65% dense nitre is slowly added dropwise
Sour 108g (1.11mol), controls 20 DEG C of stirring reaction 2h of temperature, at 20 DEG C, 300mL water is added dropwise into reaction solution, is stirred
10min, controls 25 DEG C of temperature, and 5mol/L sodium hydroxide solutions are added dropwise to neutrality, a large amount of faint yellow solids are separated out, 30min is stirred,
Suction filtration, washing, 65 DEG C of dry 56g faint yellow solids, as compound 6, yield 91.5%, mp:190~191.3 DEG C.1H-
NMR(CDCl3,400MHz)δ:1.29~1.43 (d, 6H, CH3× 2), 3.22~3.25 (m, 1H, CHCH3CH3), 3.62(s,
3H,CH3), 7.12~7.17 (m, 2H, ArH), 7.61~7.65 (m, 2H, ArH),
13.00(s,1H,OH)。
The synthesis of 2.3 formula IV compounds 7
51g (0.18mol) compound 6, potassium carbonate powder 31.9g (0.23mol), the positive fourth of acetic acid are added in 1000mL round-bottomed flasks
Ester 340mL, paratoluensulfonyl chloride 38g (0.2mol), are warming up to 45 DEG C, stirring 30min reactions are complete, add potassium carbonate powder
37.3g (0.27mol), N- methylmethanesulfonamides 25.1g (0.23mol) are warming up to 125 DEG C of back flow reactions, stir 3h, are cooled to
Room temperature, reaction solution is poured into 400mL water, stirs 10min, and point liquid, water layer is extracted 3 times with n-butyl acetate, merges organic layer, is used
Washing 2 times, saturated common salt is washed 2 times, organic phase anhydrous Na2SO4Dry, be concentrated to give crude white solid 69g, use 95% ethanol
Recrystallization, 65 DEG C of dry 64.6g white solids, as compound 7, yield 94.0%, mp:128~130 DEG C.1H-NMR
(CDCl3,400MHz)δ:1.31~1.33 (d, 6H, CH3× 2), 3.20~3.23 (m, 1H, CHCH3CH3), 3.55(s,3H,
CH3),3.61(s,3H,NCH3), 3.70 (s, 3H, SCH3), 7.14~7.18 (m, 2H, ArH), 7.67~7.70 (m, 2H,
ArH)。
2.4 Formulas I target compound I preparation
In 100mL round-bottomed flasks, 95% ethanol 40mL, 5g (0.013mol) compound 7 is added, stirring is warming up to 55 DEG C of dissolvings,
Sodium hydroxide solution (1g/3mL water) 15mL is added dropwise, 82 DEG C of back flow reactions are warming up to, 30min reactions are complete, add 10mL water, dense
Ethanol in contracting reaction solution, Liquid Residue pours into 250mL beakers, and stirring is lower to be added dropwise hydrochloric acid, adjusts pH to 3.4, stirs 5min, adds second
Acetoacetic ester is extracted, and is merged organic layer, is washed 2 times through sodium hydroxide solution, is washed 2 times, and saturated common salt is washed 2 times, and organic phase is anhydrous
Na2SO4Dry, filtering is concentrated to give 4.6g white solids, is intermediate 1, yield 95.8%, mp:211.5~212.5 DEG C.1H-
NMR(CDCl3, 400MHz) and δ:1.33~1.35 (d, 6H, CH3× 2), 3.31~3.32 (m, 1H, CHCH3CH3),3.53(s,
3H,NCH3),3.61(s,3H,SCH3), 7.12~7.17 (m, 2H, ArH), 7.73~7.76 (m, 2H, ArH)；
In 50mL round-bottomed flasks, anhydrous THF 10mL, 2g intermediates 1 (5.4mmol), potassium borohydride 0.87g are added
5min is stirred under (16.3mmol), ice bath, aluminum trichloride (anhydrous) 0.72g (5.4mmol) stirring 5min is added, is to slowly warm up to 74
DEG C, back flow reaction 4h is cooled to dropwise addition dilute hydrochloric acid solution under room temperature, ice bath and reaction is quenched, be concentrated under reduced pressure removing THF, adds second
Acetoacetic ester extracts (10mL × 3), merges organic layer, is washed 2 times through 0.1mol/L sodium hydroxide solutions, and saturated common salt is washed 2 times, is had
Machine phase anhydrous magnesium sulfate is dried, filtering, is concentrated to give 1.87g white solids, yield 97.9%, mp:134℃.Target compound I's
Total recovery is 76.2%.1H-NMR(CDCl3,400MHZ)δ:1.31~1.33 (d, 6H, CH3 × 2), 3.48 (m, 1H,
CHCH3CH3),3.50(s,3H,NCH3),3.53(s,3H,SCH3), 4.61(s,2H,CH2OH), 7.12~7.17 (m, 2H,
), ArH 7.66~7.69 (m, 2H, ArH).
Claims (5)
1. rosuvastain calcium intermediate is the preparation method of compound 1 shown in formula I,
Formula I
It is characterised in that it includes following steps：
By the compound 5 of 4-Fluorobenzaldehyde, methyl isobutyrylacetate and urea in the presence of the catalyst shown in production II；
Formula II
By compound 6 of the compound 5 in the presence of the oxidant potassium peroxydisulfate shown in production III；
Formula III
By compound 6, paratoluensulfonyl chloride and N- methylmethanesulfonamides in the presence of catalyst compound shown in production IV
7；
Formula IV
By target compound 1 of the compound 7 in the presence of the reducing agent red aluminum solution shown in normal-temperature reaction production I, then by mesh
Mark compound 1 is crystallized with crystallization solution, the target compound 1 purified；
Specifically synthetic route is：
。
2. the preparation method of rosuvastain calcium intermediate according to claim 1, it is characterised in that：Step（1）Middle institute
The catalyst stated is the mixture of methanol, stannous chloride and sulfuric acid.
3. the preparation method of rosuvastain calcium intermediate according to claim 1, it is characterised in that：Step（3）Middle institute
The catalyst stated is the mixture of potassium carbonate or potassium carbonate and n-butyl acetate.
4. the preparation method of rosuvastain calcium intermediate according to claim 1, it is characterised in that：Step（4）Middle institute
The crystallization solution stated is the mixed solution of ethyl acetate and normal heptane.
5. the preparation method of rosuvastain calcium intermediate according to claim 4, it is characterised in that：Described acetic acid second
The volume ratio of ester and normal heptane is 1:2.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109734672A (en) * | 2019-03-07 | 2019-05-10 | 烟台舜康生物科技有限公司 | A kind of synthetic method and rosuvastain calcium parent nucleus of rosuvastain calcium parent nucleus |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101948438A (en) * | 2010-08-02 | 2011-01-19 | 刘璟凌 | Novel method for preparing rosuvastatin calcium |
| CN102617481A (en) * | 2012-03-16 | 2012-08-01 | 湖南欧亚生物有限公司 | Preparation method of rosuvastatin calcium |
-
2017
- 2017-06-30 CN CN201710520711.5A patent/CN107235918A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101948438A (en) * | 2010-08-02 | 2011-01-19 | 刘璟凌 | Novel method for preparing rosuvastatin calcium |
| CN102617481A (en) * | 2012-03-16 | 2012-08-01 | 湖南欧亚生物有限公司 | Preparation method of rosuvastatin calcium |
Non-Patent Citations (1)
| Title |
|---|
| HAMID REZA MEMARIAN ET AL.: "Sono-thermal oxidation of dihydropyrimidinones", 《ULTRASONICS SONOCHEMISTRY》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109734672A (en) * | 2019-03-07 | 2019-05-10 | 烟台舜康生物科技有限公司 | A kind of synthetic method and rosuvastain calcium parent nucleus of rosuvastain calcium parent nucleus |
| CN109734672B (en) * | 2019-03-07 | 2021-12-07 | 烟台舜康生物科技有限公司 | Synthetic method of rosuvastatin calcium mother nucleus and rosuvastatin calcium mother nucleus |
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Application publication date: 20171010 |