CN101613341A - A kind of synthetic method of rosuvastatin calcium side chain key intermediate - Google Patents
A kind of synthetic method of rosuvastatin calcium side chain key intermediate Download PDFInfo
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Abstract
The invention provides a kind of preparation method of rosuvastatin calcium side chain key intermediate; with (S)-3-hydroxyl-4-chloro-butyronitrile is starting raw material; make through condensation, reduction, hydroxyl protection, condensation four-step reaction, this method reaction process is easy and simple to handle, and each goes on foot product and is easy to separation and purification; need not silicagel column and carry out purifies and separates; yield can access the intermediate of higher chemical purity and optical purity more than 80%, measures through GC; chemical purity 〉=99.4%, optical purity 〉=99.3%ee.
Description
Technical field
The present invention relates to a kind of preparation method of blood lipid-lowering medicine, relate in particular to a kind of synthetic method of statins rosuvastatin calcium side chain key intermediate.
Background technology
Rosuvastain calcium (rosuvastatin calcium) is the blood lipid-lowering medicine of clinical application; chemical name: two [(E)-and 7-[4-(4-fluorophenyl)-6-sec.-propyl-2-[methyl (methylsulfonyl) amino] pyrimidine-5-yl] (3R; 5S)-3; 5-dihydroxyl-6-heptenoic acid] calcium salt, chemical structural formula is as follows:
Be the statins of new generation of complete synthesis single enantiomer, belong to the HMG-CoA reductase inhibitor, can reduce low density cholesterol, total cholesterol, triglyceride 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, its ability to function is stronger than the statins of existing listing, and has the liver cell selectivity, good market prospect.
The synthetic method of rosuvastain calcium is existing multiple both at home and abroad, its synthetic method mostly is synthetic respectively parent nucleus and side chain, obtain target product through a series of reaction again after the butt joint, as disclosed its synthetic parent nucleus and the side chain two portions of being divided into of EP0521471, parent nucleus and side chain obtain rosuvastain calcium through Witting reaction, reduction, hydrolysis, salify.Synthetic route is as follows:
Route synthesizing rosuvastatin spit of fland calcium thus, in the reduction process of the intermediate that obtains through Witting, it is controlled that the content of chiral isomer is difficult to, and influences subsequent reactions, finally influences the optical purity of rosuvastain calcium.Therefore how obtaining high-optical-purity and stable side chain, is one of key issue in the rosuvastain calcium building-up process.
US5278313, EP0319847, US5399722, US5481009, US5998633, US6140527, EP0104750, WO0307733 provide or relate to synthesizing of side chain intermediate, but mostly exist synthetic route long, nearly 7～9 go on foot, intermediate mostly is thick thing, need multistep high vacuum (0.1mmHg) distillation and silicagel column purifying, use violent in toxicity potassium cyanide or sodium cyanide, product purity is poor, instability is difficult to problems such as industrialization production.
JP5-32680 and J.Org.Chem, 1994,59 (25) 7849-7854, the side chain synthetic method, exist synthetic difficult route long, each goes on foot intermediate and mostly is viscous liquid, separation and purification difficulty (must through multistep silicagel column purifying), product purity is poor, instability, yield is low when side chain and parent nucleus butt joint, problems such as product purity difference.
Among the preparation method of the disclosed rosuvastain calcium of WO2004052867, do not provide the synthetic method of side chain intermediate, yield is low when side chain and parent nucleus butt joint, must be through multistep silicagel column purifying.
Summary of the invention
The object of the present invention is to provide a kind of rosuvastatin calcium side chain key intermediate (4R, 6S)-the 6-[acetyl-o-methyl]-2,2-dimethyl-1,3-dioxane-4-tert.-butyl acetate] new synthetic method, structural formula is as follows:
The problems referred to above at the prior art existence, the invention provides the preparation technology that a kind of chemical formula is the compound of I, can access the intermediate of higher chemical purity and optical purity with this technology, this intermediate after reacting in order to the preparation rosuvastain calcium side chain, reaction process of the present invention is easy and simple to handle, each goes on foot product and is easy to separation and purification, need not silicagel column and carries out purifies and separates, and reaction yield improves a lot.
Rosuvastatin calcium side chain key intermediate of the present invention is achieved through the following technical solutions:
(1) (S)-3-hydroxyl-4-chloro-butyronitrile II in the presence of zinc with bromo-acetic acid tert-butyl condensation prepared (S)-6-chloro-5-hydroxyl-3-oxo hecanoic acid t-butyl ester III
At first the reaction of bromo-acetic acid tert-butyl and zinc powder makes organic zinc reagent, and organic zinc reagent and II react and make compound III.
This reaction is to carry out in certain temperature, certain solvent, and the solvent that is adopted is ethers or aromatic solvent or its mixture, for example: the mixture of one or more in tetrahydrofuran (THF), glycol dimethyl ether and the toluene; Originally be reflected under 50 ℃～110 ℃ the temperature and carry out.
The feed ratio of this reaction is: (S)-3-hydroxyl-4-chloro-butyronitrile: zinc powder: bromo-acetic acid tert-butyl=1mol: 1～3mol: 0.6～1.5mol is preferably (S)-3-hydroxyl-4-chloro-butyronitrile: zinc powder: bromo-acetic acid tert-butyl=1mol: 2.4～2.8mol: 0.9～1.1mol.
After the reaction end, drip 2mol/L hydrochloric acid in mixture, transfer pH to 5～6, behind the stirring at room 2h, add ethyl acetate and water extraction, organic phase washing, drying, concentrating under reduced pressure get compound III.
(2) compound III generation reduction reaction preparation (R, S)-6-chloro-3,5-dihydroxyl hecanoic acid t-butyl ester (compound IV)
The solvent that is adopted in step (2) reaction is ethers or alcohols or its mixture, the mixture of one or more in preferred tetrahydrofuran (THF), ether, methyl alcohol, ethanol, n-propyl alcohol, Virahol and the ethylene glycol, the more preferably mixture of one or more in tetrahydrofuran (THF), methyl alcohol and the ether.
Reductive agent is metal hydride, the boride with reductibility, the mixture of one or more in preferred sodium borohydride, POTASSIUM BOROHYDRIDE, Lithium Aluminium Hydride, diethyl methoxyl group borine, triethyl-boron and the tri butyl boron, the more preferably mixture of one or more in diethyl methoxyl group borine, sodium borohydride and the triethyl-boron.
Temperature of reaction is difference to some extent with the difference of reaction reagent, and general temperature of reaction is to carry out under-80 ℃～-30 ℃ the temperature, and preferable reaction temperature is-80 ℃～-60 ℃; Reaction times, and different, the reaction times is generally: 3～8 hours, the preferred reaction time was: 4～6 hours with the difference of reaction reagent and temperature of reaction.
The feed ratio of reaction is: compound III: borine: metal hydride=1mol: (1～2mol): (1～2mol), be preferably 1mol: 1.5mol: 1.5mol.
Last handling process: after reaction is finished, after adding acetone and the hydrogen peroxide reaction, again mixture is poured in the water, ethyl acetate extraction, the concentrating under reduced pressure solvent gets crude product, and crude product gets compound IV with the normal hexane recrystallization.
(3) under catalyst action, with acetone to compound IV carry out hydroxyl protection preparation (4R, 6S)-6-chloromethyl-2,2-dimethyl-1,3-dioxane-4-tert.-butyl acetate (compound V)
The reagent that step (3) reaction is adopted is acetone, and acetone is that solvent participates in reaction again and carries out hydroxyl protection in this reaction; Specific catalyst is a kind of or the two mixture in p-methyl benzenesulfonic acid and the Phenylsulfonic acid.
Originally be reflected under-10 ℃～50 ℃ the temperature and carry out, preferable reaction temperature is 30 ℃～50 ℃; Reaction times, and different, the reaction times was generally: 3.5～5 hours with the difference of reaction reagent and temperature of reaction.The feed ratio of reaction is: compound IV: p-methyl benzenesulfonic acid: acetone=1mol: (0.01-0.03mol): (1000-1500) mL.
After reaction was finished, mixture was poured in the water, ethyl acetate extraction, organic phase washing, dry, obtain oily matter compound V after concentrating.
(4) compound V and acetate generation condensation reaction prepare Compound I
The solvent that step (4) reaction is adopted is the mixture of single non-protonic solvent or two kinds of solvents, preferred tetrahydrofuran (THF), acetonitrile, glycol dimethyl ether and N, one or more mixture in the dinethylformamide, more preferably N, dinethylformamide.
The acetate that this reaction is adopted is one or more mixture in Potassium ethanoate, sodium-acetate and the Ammonium Acetate, preferred potassium acetate; Temperature of reaction is difference to some extent with the difference of reaction reagent, originally is reflected under 50 ℃～120 ℃ and carries out, and preferred temperature is 80 ℃～110 ℃; Reaction times, and different, the reaction times was generally: 8～13 hours with the difference of reaction reagent and temperature of reaction.
The feed ratio of reaction is: compound V: acetate=1mol: (1.1～1.3) mol.
The post-reaction treatment process is: reaction mixture poured in the frozen water, and ethyl acetate extraction, anhydrous sodium sulfate drying, decompression gets faint yellow solid after steaming solvent, and the gained solid obtains white solid I with the normal hexane recrystallization.
Technique effect of the present invention is: be feedstock production rosuvastain calcium key intermediate I with II, the raw material cheapness, be easy to get; Reaction process of the present invention is easy and simple to handle, and the part intermediate oily matter of gained need not to make with extra care and is directly used in next step production, and IV and product I are solid, the separation and purification of available ordinary method recrystallization; The product yield height, obtain higher chemical purity and optical purity (measure through GC, chemical purity 〉=99.4%, the intermediate of optical purity 〉=99.3%ee) can be used for the suitability for industrialized production of rosuvastain calcium easily.
Embodiment
Now further describe beneficial effect of the present invention by following examples, be interpreted as these embodiment and only be used for the purpose of illustration, do not limit the scope of the invention, conspicuous change and modification that while those of ordinary skills are made according to the present invention are also contained within the scope of the invention.
The preparation of embodiment 1 (S)-6-chloro-5-hydroxyl-3-oxo hecanoic acid t-butyl ester III:
Under the nitrogen protection; the 46g zinc powder is joined in the 400mL tetrahydrofuran (THF); stir 20min; add 34.5g (S)-3-hydroxyl-4-chloro-butyronitrile again; again at the slow Dropwise 5 6.2g of room temperature bromo-acetic acid tert-butyl, be warming up to back flow reaction 3h after, slowly drip 2mol/L hydrochloric acid; transfer pH to 5～6, stirring at room reaction 2h.Add 200mL ethyl acetate and 200mL water extraction, water layer 100mL ethyl acetate extraction merges organic phase, and 100mL washes once, and the organic phase anhydrous sodium sulfate drying gets oily matter III50.6g behind the pressure reducing and steaming solvent.
The preparation of embodiment 2 (S)-6-chloro-5-hydroxyl-3-oxo hecanoic acid t-butyl ester III:
Under the nitrogen protection; the 69.0g zinc powder is joined the 400mL glycol dimethyl ether; stir 20min; add 69g (S)-3-hydroxyl-4-chloro-butyronitrile again; slowly drip the 112.4g bromo-acetic acid tert-butyl in room temperature again, be warming up to back flow reaction 3.5h after, slowly drip 2mol/L hydrochloric acid; transfer pH to 5～6, stirring at room reaction 2.5h.Add 450mL ethyl acetate and 450mL water extraction, water layer 200mL ethyl acetate extraction merges organic phase, and 150mL washes once, and the organic phase anhydrous sodium sulfate drying gets oily matter III97.5g behind the pressure reducing and steaming solvent.
Embodiment 3 (R, S)-6-chloro-3, the preparation of 5-dihydroxyl hecanoic acid t-butyl ester IV
Compound III 93.8g is dissolved in 1.25L exsiccant tetrahydrofuran (THF) and 600mL methyl alcohol; be cooled to-80 ℃ under the nitrogen protection; add 427mL diethyl methoxyl group borine (tetrahydrofuran solution of 1mol/L); behind the stirring reaction 20min; add sodium borohydride 16.5g; behind reaction 3h under this temperature; add 200mL acetone and 80mL30% hydrogen peroxide, reaction system is poured in the 800mL water into ethyl acetate extraction (400mL * 3) behind the reaction 30min down for-50 ℃; merge organic phase; organic phase washing (100mL * 3), anhydrous sodium sulfate drying, decompression gets solid IV after steaming solvent; the normal hexane recrystallization gets faint yellow solid 74.6g, yield 79.5%.
Embodiment 4 (R, S)-6-chloro-3, the preparation of 5-dihydroxyl hecanoic acid t-butyl ester IV
Compound III 93.8g is dissolved in 1.3L exsiccant tetrahydrofuran (THF) and 400mL ethanol; be cooled to-65 ℃ under the nitrogen protection; add 595mL sodium borohydride (tetrahydrofuran solution of 1mol/L); behind the stirring reaction 20min; add sodium borohydride 22.6g; behind reaction 3h under this temperature; add 250mL acetone and 90mL30% hydrogen peroxide, reaction system is poured in the 800mL water into ethyl acetate extraction (400mL * 3) behind the reaction 30min down for-60 ℃; merge organic phase; organic phase washing (100mL * 3), anhydrous sodium sulfate drying, decompression gets solid IV after steaming solvent; the normal hexane recrystallization gets faint yellow solid 80.6g, yield 86.7%.
Embodiment 5 (4R, 6S)-6-chloromethyl-2,2-dimethyl-1, the preparation of 3-dioxane-4-tert.-butyl acetate V.
Compound IV 80.6g is dissolved in 400mL acetone, adds Phenylsulfonic acid 1.2g, behind 50 ℃ of reaction 4h mixture is poured in the water (800mL), ethyl acetate extraction (300mL * 3) merges organic phase, washing (200mL * 3), anhydrous sodium sulfate drying, decompression get 78.6g oily matter V after steaming solvent.
Embodiment 6 (4R, 6S)-6-chloromethyl-2,2-dimethyl-1, the preparation of 3-dioxane-4-tert.-butyl acetate V
Compound IV 80.6g is dissolved in 300mL acetone, add tosic acid 0.6g, behind 20 ℃ of reaction 4h mixture is poured in the water (800mL), ethyl acetate extraction (300mL * 3), merge organic phase, washing (200mL * 3), anhydrous sodium sulfate drying, decompression gets 73.0g oily matter V after steaming solvent.
Embodiment 7 (4R, 6S)-the 6-[acetyl-o-methyl]-2,2-dimethyl-1, the preparation of 3-dioxane-4-tert.-butyl acetate I
V78.6g is dissolved in 200mlDMF with compound, add potassium acetate 31.25g, in 100 ℃ of reaction 10h, mixture is poured in the 400mL frozen water, ethyl acetate extraction (150 * 3), anhydrous sodium sulfate drying, decompression get the 72.4g faint yellow solid after steaming solvent, and the gained solid obtains the 68.2g white solid with the normal hexane recrystallization, yield 86.7%, measure through GC: chemical purity is 99.6%, and optical purity is 99.3%ee, m.p.64～65 ℃.
Embodiment 8 (4R, 6S)-the 6-[acetyl-o-methyl]-2,2-dimethyl-1, the preparation of 3-dioxane-4-tert.-butyl acetate I
Compound V 78.6g is dissolved in the 300mL tetrahydrofuran (THF), add potassium acetate 28.87g, in 65 ℃ of reaction 13h, mixture is poured in the 400mL frozen water, ethyl acetate extraction (150 * 3), anhydrous sodium sulfate drying, decompression get the 71.4g faint yellow solid after steaming solvent, and the gained solid obtains the 65.4g white solid with the normal hexane recrystallization, yield 83.2%, measure through GC: chemical purity is 99.4%, and optical purity is 99.5%ee, m.p.63.5～65.5 ℃.
Claims (27)
1. the preparation method of a rosuvastatin calcium side chain key intermediate may further comprise the steps:
(1) (S)-3-hydroxyl-4-chloro-butyronitrile II in the presence of zinc with bromo-acetic acid tert-butyl condensation prepared (S)-6-chloro-5-hydroxyl-3-oxo hecanoic acid t-butyl ester III
(2) compound III generation reduction reaction preparation (R, S)-6-chloro-3,5-dihydroxyl hecanoic acid t-butyl ester compound IV
(3) under catalyst action, with acetone to compound IV carry out hydroxyl protection preparation (4R, 6S)-6-chloromethyl-2,2-dimethyl-1,3-dioxane-4-tert.-butyl acetate compound V
(4) compound V and acetate generation condensation reaction prepare Compound I
2. method according to claim 1 is characterized in that solvent for use in the step (1) is one or more the mixture in tetrahydrofuran (THF), glycol dimethyl ether and the toluene.
3. method according to claim 1 is characterized in that the feed ratio of used material in the step (1) is (S)-3-hydroxyl-4-chloro-butyronitrile: zinc powder: bromo-acetic acid tert-butyl=1mol: 1～3mol: 0.6～1.5mol.
4. method according to claim 1 is characterized in that the feed ratio of used material in the step (1) is: Compound I I: alkali: tert.-butyl acetate=1mol: 3.8～4.2mol: 3.8～4.2mol.
5. method according to claim 1 is characterized in that temperature of reaction is in the step (1): 50 ℃～110 ℃.
6. method according to claim 1 is characterized in that reaction solvent in the step (2) is one or more the mixture in tetrahydrofuran (THF), ether, methyl alcohol, ethanol, n-propyl alcohol, Virahol and the ethylene glycol.
7. method according to claim 1 is characterized in that reaction solvent in the step (2) is one or more the mixture in tetrahydrofuran (THF), methyl alcohol and the ether.
8. method according to claim 1 is characterized in that reductive agent in the step (2) is one or more the mixture in sodium borohydride, POTASSIUM BOROHYDRIDE, Lithium Aluminium Hydride, diethyl methoxyl group borine, triethyl-boron and the tri butyl boron.
9. method according to claim 1 is characterized in that reductive agent in the step (2) is one or more the mixture in diethyl methoxyl group borine, sodium borohydride and the triethyl-boron.
10. method according to claim 1 is characterized in that the feed ratio of reaction mass in the step (2) is: compound III: borine: metal hydride=1mol: 1～2mol: 1～2mol.
11. the post-treating method of a step (2) is characterized in that: after adding the reaction of acetone and hydrogen peroxide, again mixture is poured in the water, ethyl acetate extraction, the concentrating under reduced pressure solvent gets crude product, and crude product gets compound IV with the normal hexane recrystallization.
12. method according to claim 1 is characterized in that temperature of reaction is-80 ℃～-30 ℃ in the step (2).
13. method according to claim 1 is characterized in that temperature of reaction is-80 ℃～-60 ℃ in the step (2).
14. method according to claim 1 is characterized in that the reaction times is in the step (2): 3～8 hours.
15. method according to claim 1 is characterized in that catalyzer is a kind of or the two mixture in p-methyl benzenesulfonic acid and the Phenylsulfonic acid in the step (3).
16. method according to claim 1 is characterized in that the feed ratio of reaction mass in the step (3) is: compound IV: p-methyl benzenesulfonic acid: acetone=1mol: 0.01～0.03mol: 1000～1500mL.
17. method according to claim 1 is characterized in that temperature of reaction is-10 ℃～50 ℃ in the step (3).
18. method according to claim 1 is characterized in that temperature of reaction is 30 ℃～50 ℃ in the step (3).
19. method according to claim 1 is characterized in that the reaction times is in the step (3): 3.5～5 hours.
20. method according to claim 1 is characterized in that reaction solvent is tetrahydrofuran (THF), acetonitrile, glycol dimethyl ether and N in the step (4), one or more mixture in the dinethylformamide.
21. method according to claim 1 is characterized in that reaction solvent is N in the step (4), dinethylformamide.
22. method according to claim 1, the acetate that it is characterized in that reaction in the step (4) are one or more mixture in Potassium ethanoate, sodium-acetate and the Ammonium Acetate.
23. method according to claim 1 is characterized in that the acetate of reaction in the step (4) is potassium acetate.
24. method according to claim 1 is characterized in that the feed ratio of reaction in the step (4) is: compound V: acetate=1mol: 1.1-1.3mol.
25. method according to claim 1 is characterized in that temperature of reaction is 50 ℃～120 ℃ in the step (4).
26. method according to claim 1 is characterized in that the reaction response time is in the step (4): 8～13 hours.
27. the post-treating method of a step (4) is characterized in that reaction mixture is poured in the frozen water, ethyl acetate extraction, and anhydrous sodium sulfate drying, decompression gets faint yellow solid after steaming solvent, and the gained solid obtains white solid I with the normal hexane recrystallization.
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| US5278313A (en) * | 1992-03-27 | 1994-01-11 | E. R. Squibb & Sons, Inc. | Process for the preparation of 1,3-dioxane derivatives useful in the preparation of HMG-COA reductase inhibitors |
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| CN111675689A (en) * | 2020-06-16 | 2020-09-18 | 浙江工业大学 | Chemical synthesis method of rosuvastatin intermediate |
| CN111675689B (en) * | 2020-06-16 | 2021-08-24 | 浙江工业大学 | Chemical synthesis method of rosuvastatin intermediate |
| CN113979951A (en) * | 2021-11-24 | 2022-01-28 | 绍兴市上虞区武汉理工大学高等研究院 | Synthetic process method of rosuvastatin |
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