CN1872841A - Method for preparing Rosuvastatin Calcium and key intermediate - Google Patents
Method for preparing Rosuvastatin Calcium and key intermediate Download PDFInfo
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- CN1872841A CN1872841A CN 200510026350 CN200510026350A CN1872841A CN 1872841 A CN1872841 A CN 1872841A CN 200510026350 CN200510026350 CN 200510026350 CN 200510026350 A CN200510026350 A CN 200510026350A CN 1872841 A CN1872841 A CN 1872841A
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- 238000000034 method Methods 0.000 title claims abstract description 21
- 229960004796 rosuvastatin calcium Drugs 0.000 title 1
- LALFOYNTGMUKGG-BGRFNVSISA-L rosuvastatin calcium Chemical compound [Ca+2].CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O.CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O LALFOYNTGMUKGG-BGRFNVSISA-L 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 61
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 66
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 54
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 18
- 239000011575 calcium Substances 0.000 claims description 18
- 229910052791 calcium Inorganic materials 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 13
- 239000013078 crystal Substances 0.000 claims description 8
- 239000012065 filter cake Substances 0.000 claims description 8
- 238000001291 vacuum drying Methods 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 3
- 239000011541 reaction mixture Substances 0.000 claims description 3
- 238000010025 steaming Methods 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 abstract description 14
- 238000000746 purification Methods 0.000 abstract description 3
- 229960000672 rosuvastatin Drugs 0.000 abstract description 2
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 50
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 39
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- -1 4Be hydrogen Chemical class 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 238000006386 neutralization reaction Methods 0.000 description 5
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 4
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N methylene hexane Natural products CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 4
- 238000007039 two-step reaction Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- XORXDJBDZJBCOC-UHFFFAOYSA-N azanium;acetonitrile;acetate Chemical group [NH4+].CC#N.CC([O-])=O XORXDJBDZJBCOC-UHFFFAOYSA-N 0.000 description 3
- 229910000085 borane Inorganic materials 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 210000005229 liver cell Anatomy 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 3
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 2
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 2
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 229960003765 fluvastatin Drugs 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 229960002855 simvastatin Drugs 0.000 description 2
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 108010052832 Cytochromes Proteins 0.000 description 1
- 102000018832 Cytochromes Human genes 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 208000000563 Hyperlipoproteinemia Type II Diseases 0.000 description 1
- 102100024640 Low-density lipoprotein receptor Human genes 0.000 description 1
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 206010045261 Type IIa hyperlipidaemia Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000003113 alkalizing effect Effects 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001669 calcium Chemical class 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002019 doping agent Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 201000001386 familial hypercholesterolemia Diseases 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000002891 organic anions Chemical class 0.000 description 1
- 239000001301 oxygen Chemical group 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
This invention provides a method for preparing rosuvastatin intermediate compound I-XI. The method can ensure a high purity of I-XI, thus ensuring the completeness of the stereoselectivity in subsequent reactions. Although the yield of I-XII from I-X in this invention is a little lower than that in the invention EP 0,521,471 A1, the purification of I-XII only needs a low-efficiency chromatographic column. The method thus has such advantages as low cost and high efficiency.
Description
Technical field
The present invention relates to the preparation of rosuvastain calcium (Rosuvastatin), especially wherein the preparation method of a key intermediate.
Background technology
The structure I compound that shows below is a kind of HMG-CoA reductase inhibitor, is used to treat that atherosclerosis, blood fat are too high, in familial hypercholesterolemia and the similar disease.
Wherein, R
1Be C
1-6Alkyl, aryl or aralkyl (C1-C6); R
2And R
3Be hydrogen, C
1-6Alkyl or aralkyl (C1-C6); R
4Be hydrogen, C
1-6Alkyl (C1-C6) or connect the salt that does not have toxicity and do not influence pharmacological action; X is sulphur, oxygen or alkylsulfonyl or substituent imino-is arranged.
The structure I compound comprises that lovastatin (mevinolin) is (by United States Patent (USP) 4,231,938 disclose), Pravastatin (pravatatin) is (by United States Patent (USP) 4,346,227 disclose), Simvastatin (simvastatin) is (by United States Patent (USP) 4,444,784 disclose), fluvastatin (fluvastatin) (by world patent 2,202,846 disclose).
Structure I I compound is a rosuvastain calcium:
Rosuvastain calcium is a single enantiomorph (3R, 5S) the calcium salt of carboxylic acid through alkalizing and, dihydric heptene acid in the molecule partly is the general character drug effect base of Statins, rest part is different from other Statins, and the existence of its Semi-polarity methanesulfonamido makes it present relatively low lipotropy character.The wetting ability of rosuvastain calcium means that its passive diffusibility is lower, so be difficult to enter non-liver cell.But it can be the liver cell absorption by selectivity organic anion fortune process of assembling, has the advantages that selectivity distributes and acts on HMG-CoA reductase enzyme in the liver.The relative water-soluble nature of rosuvastain calcium also makes it promptly needing can avoid cytochrome P before elimination
450Extensive metabolic defective is so its drug interaction potentiality also reduce greatly.
It is stronger than existing listing statins that rosuvastain calcium suppresses the effect of HMG-CoA reductase enzyme, and have the liver cell selectivity, and market outlook are fairly good.But because it has the chemical structure of two chiral carbon, in preparation suitable difficulty is arranged, the control of its content of isomer is very strict, needs the technology that more can guarantee its optical texture and prepares.
The preparation method of rosuvastain calcium such as European patent EP 0,521,471 A1 are described, can be illustrated as follows:
Wherein, the preparation method of intermediate compound I-XI is: Compound I-X is dissolved in acetonitrile, gets solution 1; Dropwise 48% (v/w) HF aqueous solution is added acetonitrile, get solution 2; Under condition of ice bath, solution 2 is dropwise joined in the solution 1; Dropwise post-heating to room temperature, stir 1.5hr; Neutralize with sodium carbonate solution; Use extracted with diethyl ether; Organic layer washs with sodium chloride solution, and drying removes solvent under reduced pressure, promptly gets Compound I-XI.
Then, gained Compound I-XI and the reaction of diethyl methoxyl group borine make Compound I-XII.The two-step reaction total yield is about 85.2%.
Compound I-XI promptly directly carries out next step reaction without making with extra care in the above method.Then single step reaction is to introduce the gene that contains second chiral carbon on Compound I-XI, promptly carries out the stereoselectivity reaction, and this is the committed step that guarantees the rosuvastain calcium optical texture.Experiment shows, without purified Compound I-XI (developping agent sherwood oil: on the TLC plate ethyl acetate=2: 1) except that having the principal spot at the Rf=0.48 place, at Rf=0.64 and Rf=0.40 place the impurity spot is arranged, these impurity enter the reaction of back one step generation Compound I-XII, then produce plurality of impurities, and measure manyly, can influence the thoroughness of stereoselective reaction, cause that 3 of unwanted dihydric heptene acid groups go up the enantiomer foreign matter contents and raise.And in case after the reaction that generates Compound I-XII finished, because by product and purpose product I-XII structural similitude, Rf was close, and dopant species is many, content is big, it is also very difficult with their removal promptly to use silica gel column chromatography to cross the post method.Like this, in order to reach the purifying purpose, for example reach 90% above purity, must adopt post to imitate (being the ratio of chromatography column length and diameter of section) very high chromatography column, this has not only prolonged the production cycle, and has improved running cost, has reduced production efficiency on the whole.
Summary of the invention:
In order to overcome the above problems, the invention provides a kind of method for preparing midbody compound I-XI, guaranteed the pure of Compound I-XI, guaranteed that thus the subsequent reactions neutral body is optionally complete.In industrialization, though make the yield of Compound I-XII two-step reaction a little less than EP 0,521 by Compound I-X, 471A1, but in the purifying of Compound I-XII, only need post to imitate lower chromatography column and get final product, reduce production cost thus, and shortened the production cycle, improved overall efficiency.
Specifically, the invention provides a kind of preparation rosuvastain calcium midbody compound I-XI method, its step comprises:
Provide Compound I-X, reacting generating compound I-XI as follows:
Use the extracted with diethyl ether reaction mixture;
Isolate organic phase, steaming desolventizes, and makes the concentrated solution that contains Compound I-XI;
In the gained concentrated solution, add toluene/ether mixture, be stirred to dissolving under the room temperature;
Be cooled to then and crystallize under the 0-4 ℃ of condition fully;
Filter, get filter cake vacuum-drying, get the purified compound I-XI of yellow crystals shape;
Wherein, concentrated solution: toluene/ether mixture (w/v)=1: 1～1: 1.5 was good with 1: 1.5; Toluene: ether (v/v)=3: 1～1: 1 was good with 2: 1.
The present invention also provides a kind of method for preparing rosuvastain calcium, comprising:
Prepare midbody compound I-XI with the inventive method, and make rosuvastain calcium by gained Compound I-XI.
Embodiment
Embodiment 1:
According to EP 0,521, the described preparation Compound I-X of 471 A1.Take by weighing 16g Compound I-X, it is dissolved in the 100ml acetonitrile, get solution 1.Under condition of ice bath, 20ml 48% (w/v) the HF aqueous solution is added the 380ml acetonitrile, get solution 2.Solution 1 is dropwise added in the solution 2 under condition of ice bath.Dropwise post-heating to room temperature, stir 1.5hr.Use Na then
2CO
3Extracted with diethyl ether is used in neutralization.Separate and the results organic layer,, remove solvent under reduced pressure, get the 14.6ml concentrated solution with sodium-chlor washing, drying.3: 2 (v/v) mixture 14.6ml that add toluene/ether in concentrated solution, concentrated solution: the ratio (w/v) of mixed solution is 1: 1.Be stirred to dissolving under the room temperature.Be cooled to 0-4 ℃ of crystallization.Get the reacting liquid filtering after the crystallization, get filtrate point TLC plate, if immaculate on the corresponding Rf value of the Compound I-XI position can assert that crystallization is complete.Filter, get filter cake vacuum-drying, get the Compound I-XI of yellow crystals shape, 12.8g.The purity that records with HPLC (with dissolve with methanol, moving phase is ammonium acetate-acetonitrile solution) is 98.7%.
HNMR(CDCl
3)δ：1.28(d，6H)，2.52(m，2H)，2.73(m，2H)，3.36(hept，1H)，3.51(s，3H)，3.59(s，3H)，3.72(s，3H)，4.48(m，1H)，6.16(d，1H)，7.13(t，2H)，7.59(m，2H)，7.63(d，1H)。
Embodiment 2:
30g Compound I-X is dissolved in the 800ml acetonitrile, adds 20ml 48% (w/v) HF solution, under room temperature, react 10hr.The molten cooling of cryosel adds NaHCO down
3, pH is transferred to 7, use extracted with diethyl ether.Separate and the results organic layer,, use anhydrous Na with the saturated common salt washing
2SO
4Drying is filtered, and removes solvent under reduced pressure, gets 26.8g oily concentrated solution.2: 1 (v/v) mixture 40.2ml that add toluene/ether in concentrated solution, concentrated solution: the ratio (w/v) of mixed solution is 2: 3, is stirred to dissolving under the room temperature.Be cooled to 0-4 ℃ of sufficient crystallising.Filter, get filter cake vacuum-drying, get the Compound I-XI of yellow crystals shape, 22.5g.As previously mentioned with HPLC mensuration, purity is 98.8%.
HNMR(CDCl
3)δ：1.28(d，6H)，2.52(m，2H)，2.73(m，2H)，3.36(hept，1H)，3.51(s，3H)，3.59(s，3H)，3.72(s，3H)，4.48(m，1H)，6.16(d，1H)，7.13(t，2H)，7.59(m，2H)，7.63(d，1H)。
Embodiment 3:
20g Compound I-X is dissolved in the 125ml acetonitrile, gets solution 1.Under condition of ice bath, 25ml48% (w/v) the HF aqueous solution is added the 475ml acetonitrile, get solution 2.Solution 1 is dropwise added in the solution 2 under condition of ice bath, dropwise post-heating, stir 1.5hr to room temperature.Use Na
2CO
3Extracted with diethyl ether is used in neutralization.Separate and the results organic layer,, remove solvent under reduced pressure, get the 18.3g concentrated solution with sodium-chlor washing, drying.Add toluene in concentrated solution: 3: 1 (v/v) mixtures of ether 27.5ml, concentrated solution: the ratio (w/v) of mixed solution is 1: 1.5, dissolves in the room temperature.Be cooled to 0-4 ℃ of sufficient crystallising then.Filter, get filter cake vacuum-drying, get the Compound I-XI of yellow crystals shape, 16.1g.As previously mentioned with HPLC mensuration, purity 98.9%.
HNMR(CDCl
3)δ：1.28(d，6H)，2.52(m，2H)，2.73(m，2H)，3.36(hept，1H)，3.51(s，3H)，3.59(s，3H)，3.72(s，3H)，4.48(m，1H)，6.16(d，1H)，7.13(t，2H)，7.59(m，2H)，7.63(d，1H)。
Embodiment 4:
40g Compound I-X is dissolved in the 250ml acetonitrile, gets solution 1.Under condition of ice bath, 50m148% (w/v) the HF aqueous solution is added the 950ml acetonitrile, get solution 2.Solution 1 is dropwise added in the solution 2 under condition of ice bath, dropwise post-heating, stir 1.5hr to room temperature.Use Na
2CO
3Extracted with diethyl ether is used in neutralization.Separate and the results organic layer,, remove solvent under reduced pressure, get the 37.3g concentrated solution with sodium-chlor washing, drying.1: 1 (v/v) mixture 56.0ml that adds toluene/ether in concentrated solution, concentrated solution: the ratio (w/v) of mixed solution is 1: 1.5, dissolves in the room temperature.Be cooled to 0-4 ℃ of sufficient crystallising.Filter, get filter cake vacuum-drying, get the Compound I-XI of yellow crystals shape, 32.5g.As previously mentioned with HPLC mensuration, purity is 99.0%.
HNMR(CDCl
3)δ：1.28(d，6H)，2.52(m，2H)，2.73(m，2H)，3.36(hept，1H)，3.51(s，3H)，3.59(s，3H)，3.72(s，3H)，4.48(m，1H)，6.16(d，1H)，7.13(t，2H)，7.59(m，2H)，7.63(d，1H)。
Embodiment 5:
50g Compound I-X is dissolved in the 312.5ml acetonitrile, gets solution 1.Under condition of ice bath, 62.5ml48% (w/v) the HF aqueous solution is added the 1187.5ml acetonitrile, get solution 2.Solution 1 is dropwise added in the solution 2 under condition of ice bath.Dropwise post-heating to room temperature, stir 1.5hr.Use Na
2CO
3Extracted with diethyl ether is used in neutralization.Separate and the results organic layer,, remove solvent under reduced pressure, get the 46.1g concentrated solution with sodium-chlor washing, drying.2: 1 (v/v) mixture 69.2ml that add toluene/ether in concentrated solution, concentrated solution: the ratio (w/v) of mixed solution is 1: 1.5, dissolves in the room temperature.Be cooled to 0-4 ℃ of sufficient crystallising.Filter, get filter cake vacuum-drying, get the Compound I-XI of yellow crystals shape, 41.6g.As previously mentioned with HPLC mensuration, purity 99.1%.
HNMR(CDCl
3)δ：1.28(d，6H)，2.52(m，2H)，2.73(m，2H)，3.36(hept，1H)，3.51(s，3H)，3.59(s，3H)，3.72(s，3H)，4.48(m，1H)，6.16(d，1H)，7.13(t，2H)，7.59(m，2H)，7.63(d，1H)。
Comparing embodiment
Contrast:
10g Compound I-X is dissolved in the 62.5ml acetonitrile, gets solution 1.Under condition of ice bath, 12.5ml48% (w/v) the HF aqueous solution is added the 237.5ml acetonitrile, get solution 2.Solution 1 is dropwise added in the solution 2 under condition of ice bath.Dropwise post-heating to room temperature, stir 1.5hr.Use Na
2CO
3Extracted with diethyl ether is used in neutralization.Separate and the results organic layer,, remove solvent under reduced pressure, get 9.2g Compound I-XI concentrated solution with sodium-chlor washing, drying.As previously mentioned with HPLC mensuration, purity is 92%.
1M diethyl methoxyl group borine reaction with gained concentrated solution 9.2g and 18.4ml obtains 6.95g Compound I-XII.The two-step reaction total yield is about 85.2%.
HNMR(CDCl
3)δ：1.27(d，J＝7，6H)，1.52(m，2H)，2.47(d，J＝6，2H)，3.36(hept，J＝2，1H)，3.52(s，3H)，3.57(s，3H)，3.73(s，3H)，4.2(m，1H)，4.43(m，1H)，5.45(dd，J＝5，16，1H)，6.64(dd，J＝2，16，1H)，7.09(m，2H)，7.64(m，2H)。
With purification by silica gel column chromatography gained Compound I-above purity of XII to 90% (the HPLC method is measured, and with dissolve with methanol, moving phase is ammonium acetate-acetonitrile solution).Then, as EP 0,521,471 A1 are described, carry out subsequent reactions, until making rosuvastain calcium.
The present invention:
With 10g embodiment 5 gained Compound I-XI and the reaction of 8.3g diethyl methoxyl group borine, make 6.67g Compound I-XII.The two-step reaction total yield is about 81.8%.
HNMR(CDCl
3)δ：1.27(d，J＝7，6H)，1.52(m，2H)，2.47(d，J＝6，2H)，3.36(hept，J＝2，1H)，3.52(s，3H)，3.57(s，3H)，3.73(s，3H)，4.2(m，1H)，4.43(m，1H)，5.45(dd，J＝5，16，1H)，6.64(dd，J＝2，16，1H)，7.09(m，2H)，7.64(m，2H)。
With purification by silica gel column chromatography gained Compound I-above purity of XII to 90% (the HPLC method is measured, and with dissolve with methanol, moving phase is ammonium acetate-acetonitrile solution).Then, as EP 0,521,471 A1 are described, carry out subsequent reactions, until making rosuvastain calcium.
Table 1
| The present invention | Contrast | |
| Compound I-XI purity (%) | 99.1 | 92 |
| Compound I-X is to the total yield (%) of Compound I-XII | 81.8 | 85.2 |
| The required post of purifying compounds I-XII () purity＞90% is imitated (in chromatography column Φ=10cm, the length of chromatography column) | Low (15cm) | High (40-45cm) |
| The amount of every purifying 10g Compound I-XII used silica gel (300 order) is (in chromatography column Φ=10cm) (g) | 450 | 1200 |
| Purifying compounds I-XII required time (hr) | 8 | 20 |
| Impurity (%) (measuring) in the reaction gained rosuvastain calcium except that isomer with the HPLC method | 1 | 1.5 |
| Rosuvastain calcium isomer impurities content (%) (measuring) with HPLC method chiral column | 0.5 | 1 |
Claims (6)
1. one kind prepares rosuvastain calcium midbody compound I-XI method,
Its step comprises:
Provide Compound I-X, reacting generating compound I-XI as follows:
Use the extracted with diethyl ether reaction mixture;
Isolate organic phase, steaming desolventizes, and makes the concentrated solution that contains Compound I-XI;
In the gained concentrated solution, add toluene/ether mixture, be stirred to dissolving under the room temperature;
Be cooled to and crystallize under the 0-4 ℃ of condition fully;
Filter, get filter cake vacuum-drying, get the purified compound I-XI of yellow crystals shape;
Wherein, concentrated solution: toluene/ether mixture (w/v)=1: 1～1: 1.5, toluene: ether (v/v)=3: 1～1: 1.
2. the method for claim 1, wherein concentrated solution: toluene/ether mixture (w/v)=1: 1.5.
3. the method for claim 1, wherein toluene: ether (v/v)=2: 1.
4. method for preparing rosuvastain calcium comprises:
Provide Compound I-X, reacting generating compound I-XI as follows:
Use the extracted with diethyl ether reaction mixture;
Isolate organic phase, steaming desolventizes and makes the concentrated solution that contains Compound I-XI;
In the gained concentrated solution, add toluene/ether mixture, be stirred to dissolving under the room temperature;
Be cooled to then and crystallize under the 0-4 ℃ of condition fully;
Filter, get filter cake vacuum-drying, get the purified compound I-XI of yellow crystals shape;
Compound I-XI makes rosuvastain calcium by gained;
Wherein, concentrated solution: toluene/ether mixture (w/v)=1: 1～1: 1.5, toluene: ether (v/v)=3: 1～1: 1.
5. method as claimed in claim 4, wherein, concentrated solution: toluene/ether mixture (w/v)=1: 1.5.
6. method as claimed in claim 4, wherein, toluene: ether (v/v)=2: 1.
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| US7582759B2 (en) | 2005-02-22 | 2009-09-01 | Teva Pharmaceutical Industries Ltd. | Diastereomeric purification of rosuvastatin |
| WO2009143776A1 (en) | 2008-05-27 | 2009-12-03 | 常州制药厂有限公司 | Preparation method of rosuvastatin calcium and its intermediates |
| US7777034B2 (en) | 2003-11-24 | 2010-08-17 | Teva Pharmaceutical Industries Ltd. | Crystalline ammonium salts of rosuvastatin |
| WO2009128091A3 (en) * | 2008-02-20 | 2010-11-04 | Matrix Laboratories Limited | Crystalline form of(7-[4-(4-fluorophenyl)-6-isopropyl-2-(n- methyl-n-methylsulfonylamino)pyrimidin-5-yl]-(3r,5s)- dihydroxy-(e)-6-heptenoic acid intermediate, process for preparing the same and use thereof |
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| CN101955463A (en) * | 2010-08-04 | 2011-01-26 | 重庆博腾制药科技股份有限公司 | Method for preparing rosuvastatin calcium intermediate |
| CN101591302B (en) * | 2008-05-27 | 2011-08-31 | 常州制药厂有限公司 | Preparation technique of heptenoic acid ester derivative |
| CN103298793A (en) * | 2010-11-29 | 2013-09-11 | 埃吉斯药物股份公开有限公司 | Method for the preparation of high-purity pharmaceutical intermediates |
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| US7777034B2 (en) | 2003-11-24 | 2010-08-17 | Teva Pharmaceutical Industries Ltd. | Crystalline ammonium salts of rosuvastatin |
| US7851624B2 (en) | 2003-12-24 | 2010-12-14 | Teva Pharamaceutical Industries Ltd. | Triol form of rosuvastatin and synthesis of rosuvastatin |
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| US7582759B2 (en) | 2005-02-22 | 2009-09-01 | Teva Pharmaceutical Industries Ltd. | Diastereomeric purification of rosuvastatin |
| US7868169B2 (en) | 2005-08-16 | 2011-01-11 | Teva Pharmaceutical Industries, Ltd. | Crystalline rosuvastatin intermediate |
| WO2009128091A3 (en) * | 2008-02-20 | 2010-11-04 | Matrix Laboratories Limited | Crystalline form of(7-[4-(4-fluorophenyl)-6-isopropyl-2-(n- methyl-n-methylsulfonylamino)pyrimidin-5-yl]-(3r,5s)- dihydroxy-(e)-6-heptenoic acid intermediate, process for preparing the same and use thereof |
| WO2009143776A1 (en) | 2008-05-27 | 2009-12-03 | 常州制药厂有限公司 | Preparation method of rosuvastatin calcium and its intermediates |
| CN101591302B (en) * | 2008-05-27 | 2011-08-31 | 常州制药厂有限公司 | Preparation technique of heptenoic acid ester derivative |
| US8653265B2 (en) | 2008-05-27 | 2014-02-18 | Changzhou Pharmaceutical Factory | Preparation method of rosuvastatin calcium and its intermediates |
| US8765947B2 (en) | 2008-05-27 | 2014-07-01 | Changzhou Pharmaceutical Factory | Preparation method of Rosuvastatin calcium and its intermediates |
| CN101955463A (en) * | 2010-08-04 | 2011-01-26 | 重庆博腾制药科技股份有限公司 | Method for preparing rosuvastatin calcium intermediate |
| CN103298793A (en) * | 2010-11-29 | 2013-09-11 | 埃吉斯药物股份公开有限公司 | Method for the preparation of high-purity pharmaceutical intermediates |
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