CN114195670A - Refining method of atorvastatin mother nucleus M4 - Google Patents
Refining method of atorvastatin mother nucleus M4 Download PDFInfo
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- CN114195670A CN114195670A CN202111659985.5A CN202111659985A CN114195670A CN 114195670 A CN114195670 A CN 114195670A CN 202111659985 A CN202111659985 A CN 202111659985A CN 114195670 A CN114195670 A CN 114195670A
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- atorvastatin
- mother nucleus
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- acid
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- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 title claims abstract description 78
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 title claims abstract description 78
- 229960005370 atorvastatin Drugs 0.000 title claims abstract description 78
- 238000000034 method Methods 0.000 title claims abstract description 44
- 238000007670 refining Methods 0.000 title claims abstract description 29
- 239000012043 crude product Substances 0.000 claims abstract description 37
- 239000012046 mixed solvent Substances 0.000 claims abstract description 33
- 239000000047 product Substances 0.000 claims abstract description 25
- 238000004537 pulping Methods 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 238000001953 recrystallisation Methods 0.000 claims abstract description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 38
- 229960000583 acetic acid Drugs 0.000 claims description 19
- 239000012362 glacial acetic acid Substances 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 238000001035 drying Methods 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 12
- 238000002156 mixing Methods 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 7
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 238000004321 preservation Methods 0.000 claims description 6
- 238000000967 suction filtration Methods 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 126
- 238000006243 chemical reaction Methods 0.000 abstract description 53
- 230000008569 process Effects 0.000 abstract description 18
- 150000001875 compounds Chemical class 0.000 abstract description 16
- 238000002844 melting Methods 0.000 abstract description 10
- 230000008018 melting Effects 0.000 abstract description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 abstract description 8
- 238000002425 crystallisation Methods 0.000 abstract description 7
- 230000008025 crystallization Effects 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 abstract description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 abstract description 4
- 235000011181 potassium carbonates Nutrition 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 239000011736 potassium bicarbonate Substances 0.000 abstract description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 abstract description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 abstract description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 abstract description 3
- 150000003839 salts Chemical class 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000012452 mother liquor Substances 0.000 abstract description 2
- 239000001103 potassium chloride Substances 0.000 abstract description 2
- 235000011164 potassium chloride Nutrition 0.000 abstract description 2
- 238000012797 qualification Methods 0.000 abstract description 2
- 230000001276 controlling effect Effects 0.000 description 24
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 20
- 229910052731 fluorine Inorganic materials 0.000 description 18
- 239000011737 fluorine Substances 0.000 description 18
- 125000000950 dibromo group Chemical group Br* 0.000 description 13
- 230000001105 regulatory effect Effects 0.000 description 12
- 238000001514 detection method Methods 0.000 description 11
- BXWLVQXAFBWKSR-UHFFFAOYSA-N 2-methoxy-5-methylsulfonylbenzoic acid Chemical compound COC1=CC=C(S(C)(=O)=O)C=C1C(O)=O BXWLVQXAFBWKSR-UHFFFAOYSA-N 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 230000008054 signal transmission Effects 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- OJRHUICOVVSGSY-RXMQYKEDSA-N (2s)-2-chloro-3-methylbutan-1-ol Chemical compound CC(C)[C@H](Cl)CO OJRHUICOVVSGSY-RXMQYKEDSA-N 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 229960001770 atorvastatin calcium Drugs 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 description 1
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 108010028554 LDL Cholesterol Proteins 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229940059260 amidate Drugs 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000006115 defluorination reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 108010022197 lipoprotein cholesterol Proteins 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- HNNFDXWDCFCVDM-UHFFFAOYSA-N methyl 4-methyl-3-oxopentanoate Chemical compound COC(=O)CC(=O)C(C)C HNNFDXWDCFCVDM-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- DFIWJEVKLWMZBI-UHFFFAOYSA-M sodium;dihydrogen phosphate;phosphoric acid Chemical group [Na+].OP(O)(O)=O.OP(O)([O-])=O DFIWJEVKLWMZBI-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
Abstract
The invention belongs to the technical field of drug synthesis processes, and particularly relates to a refining method of atorvastatin mother nucleus M4. According to the invention, the DCS reaction kettle system is adopted to adjust the pH value of the system, so that the target product M4 can be effectively inhibited from being damaged under acid-base conditions, the generation of unknown impurities is reduced, and the refining qualification rate is improved. The method can remove potassium carbonate, potassium bicarbonate, potassium chloride and other inorganic salts in the atorvastatin mother nucleus M4 (namely the compound VI) crude product 1 synthesized by a convergence method in the pulping process, and effectively removes and reduces impurities and improves the refining yield by utilizing a mixed solvent in the recrystallization process. The method has the advantages of simple post-treatment process, high yield, reutilization of recovered solvent and crystallization mother liquor, suitability for industrial production, high chemical purity of the obtained product, low impurity content, high melting point, short melting range and good stability.
Description
Technical Field
The invention belongs to the technical field of drug synthesis processes, and particularly relates to a refining method of atorvastatin mother nucleus M4.
Background
Atorvastatin calcium is a statin lipid-lowering drug jointly developed by WarnerLambert and Prizer in the United states, can strongly inhibit the activity of hydroxymethylglutaryl coenzyme A (HMKG-CoA) reductase, and obviously reduces the content of total cholesterol and low-density lipoprotein cholesterol. The medicine has the advantages of small toxic and side effects, unique action mechanism, good tolerance and very wide market application prospect.
The atorvastatin mother nucleus M4 is a mother ring intermediate for synthesizing atorvastatin calcium, and the molecular formula is C26H24FNO3The chemical name is: 4-fluoro-alpha- [ 2-methyl-1-oxopropyl radical]- γ -oxo-N, β -diphenylbenzenebutanamide having the formula:
the preparation method of atorvastatin mother nucleus M4 mainly comprises two methods: linear synthesis and convergent synthesis. Compared with the conventional method, the convergent synthesis method has the advantages of easy quality control, simple and feasible operation, easy separation and purification of target products, and economy and practicability, and is a mainstream synthetic route for synthesizing atorvastatin mother nucleus M4 at present.
In the prior art, a preparation process of atorvastatin mother nucleus M4 is reported more, but a refining process of the atorvastatin mother nucleus M4 is described rarely. The atorvastatin mother nucleus M4 contains a plurality of functional groups, is sensitive to pH value, and in the purification process of the atorvastatin mother nucleus M4, new unknown impurities are generated due to different pH values and are difficult to effectively remove, so that the melting point of the M4 product is unqualified. A large number of experimental researches find that impurities generated in the process of synthesizing atorvastatin mother nucleus M4 are closely related to the pH value and the water content in a system. How to purify atorvastatin mother nucleus M4 and improve yield and purity is an urgent technical problem to be solved.
In the prior art, the synthetic route of atorvastatin mother nucleus M4 is as follows:
the method comprises the following specific steps: 1) performing a friedel-crafts reaction on phenylacetyl chloride and fluorobenzene under the condition of Lewis acid to obtain a compound II; 2) brominating the compound II to obtain a compound III; 3) reacting methyl isobutyrylacetate (compound IV) with aniline to obtain an amidate V; 4) synthesizing a compound VI (atorvastatin mother nucleus M4) from the compound V and a compound III in an alkaline environment; wherein, potassium carbonate is used for providing an alkaline environment in the step 4), and alkaline inorganic salts such as potassium carbonate, potassium bicarbonate, potassium bromide and the like are wrapped in the compound VI in the reaction process.
Meanwhile, the synthesis route can generate a plurality of impurities in the process of preparing the compound VI, and the main impurity components are as follows:
wherein, the impurity five is generated when excessive bromine is dripped in the bromination procedure in the step 2); impurities one to four are generated in step 4). In order to obtain high-quality atorvastatin mother nucleus M4, relevant impurities (impurity I to impurity V) in the synthesis process are effectively removed, and a crude atorvastatin mother nucleus M4 product needs to be refined.
Meanwhile, research personnel analyze and show that unknown impurities (RRT1.15) exist in the refining process of the atorvastatin mother nucleus M4 crude product through an HPLC method, the impurities are difficult to remove after being produced, the quality of a final product is directly influenced, the problems that the melting point is unqualified in the product detection process, the one-time refining qualification rate of the product is low and the like are caused, subsequent reworking treatment is needed, the production efficiency is directly influenced, and the product cost is increased.
In order to improve the single-batch yield and capacity, the invention adopts a mixed solvent method to refine the crude atorvastatin mother nucleus M4, wherein one solvent is used for improving the solubility, the other solvent is used for improving the crystallization yield, and the yield and the capacity are improved by improving the feeding amount of the crude product with the same volume while maintaining high refining rate.
Disclosure of Invention
In order to solve the technical problems in the prior art, related impurities (impurity I to impurity V) in the atorvastatin mother nucleus M4 crude product are effectively removed, and meanwhile, unknown impurities (RRT1.15) are prevented from being generated in the refining process, the invention provides a refining method of the atorvastatin mother nucleus M4 crude product, which adopts a mode of accurately controlling pH twice to prevent the product from being damaged by poor pH of a system and generating the unknown impurities (RRT 1.15).
In order to achieve the purpose, the invention adopts the following technical scheme:
a refining method of atorvastatin mother nucleus M4 comprises the following steps:
(1) mixing the atorvastatin mother nucleus M4 (namely compound VI) crude product 1 with water, stirring for dissolving, and adding acid to adjust the pH value to 5.60-6.40; then pulping for 2-3 hours at room temperature, centrifuging and drying to obtain a crude product 2 of atorvastatin mother nucleus M4;
(2) mixing the atorvastatin mother nucleus M4 crude product 2 in the step (1) with a mixed solvent, stirring for dissolving, and adding acid to adjust the pH value to 5.7-5.8; and then carrying out hot reflux for 1-3 hours at the temperature of 35-50 ℃, carrying out suction filtration while the mixture is hot, concentrating the filtrate at the temperature of 60-65 ℃ under normal pressure, recovering the mixed solvent, cooling the concentrated solution to 0-10 ℃, carrying out heat preservation and recrystallization for 1-3 hours, centrifuging, and drying to obtain the refined atorvastatin mother nucleus M4 (compound VI).
Further, the mass ratio of the atorvastatin mother nucleus M4 crude product 1 to water in the step (1) is 1: 3.0 to 5.0.
Further, in the step (1), inorganic acid is adopted to adjust the pH value, and the inorganic acid is hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid.
Further preferably, the pH value is adjusted by hydrochloric acid within a range of 5.95-6.15.
Further, drying in the step (1) until the water content is less than or equal to 1 percent.
Further, in the step (2), a mixed solvent is added as a recrystallization solvent to recrystallize the crude atorvastatin mother nucleus M4 product 2.
Further, the mixed solvent in the step (2) is a mixed solvent of methanol and dichloromethane, wherein the mass fraction of the methanol is 40% -60%, and preferably 45%.
Further, in the step (2), the mass ratio of the atorvastatin mother nucleus M4 crude product 2 to the mixed solvent is 1: 3-3.5, the volume ratio is 1: 2 to 2.5.
Further, in the step (2), organic acid is adopted to adjust the pH value, and the organic acid is glacial acetic acid, tartaric acid, oxalic acid and propionic acid.
Further preferably, glacial acetic acid is selected to adjust the pH value to 5.75.
Further, the solvent amount recovered by the normal pressure concentration in the step (2) is 55-65% of the original solvent amount.
Further, in the step (2), the drying temperature is 50-65 ℃, and the drying time is 3-5 hours.
Furthermore, in the invention, acid is added to adjust the pH value of the reaction system in the process of refining the crude atorvastatin mother nucleus M4 product, and the addition amount of the acid needs to be accurately controlled.
Specifically, the DCS reaction kettle system capable of regulating and controlling the pH value comprises a reaction kettle, a first adding tank, a second adding tank and DCS control equipment;
the first adding tank is filled with inorganic acid, and the second adding tank is filled with organic acid;
a stirring shaft and a stirring paddle are arranged in the reaction kettle, a top cover of the reaction kettle is provided with a first feeding port and a second feeding port, the output end of the first feeding tank is communicated with the first feeding port on the top cover of the reaction kettle through a first feeding pipe, and the output end of the second feeding tank is communicated with the second feeding port on the top cover of the reaction kettle through a second feeding pipe;
a top cover of the reaction kettle is also provided with a pH meter with a signal transmission module, and a measuring end of the pH meter extends into the reaction kettle;
the DCS control equipment comprises a DCS control module, a computing unit is arranged in the DCS control module, and the signal output end of the pH meter is communicated with the signal input end of the DCS control module in the DCS control equipment;
be equipped with first automatically controlled valve on the first filling tube, be equipped with the second automatically controlled valve on the second filling tube, DCS control module's signal output part is equipped with two branches, and first branch is linked together with the signal input part of first automatically controlled valve, and the second branch is linked together with the signal input part of second automatically controlled valve.
Furthermore, a first control valve is further arranged on the first feeding pipe, and a second control valve is further arranged on the second feeding pipe.
Further, the pH meter with the signal transmission module is Z-PH 100M.
Further, the model of the first electric control valve and the model of the second electric control valve are AOX-Q-050.
Specifically, the DCS control device of the present invention may be implemented by a conventional device in the prior art, and the structure and components of the DCS control device are not the point of the present invention, and thus are not described in detail.
Compared with the prior art, the invention has the beneficial effects that:
1. the refining method of the atorvastatin mother nucleus M4 crude product can remove potassium carbonate, potassium bicarbonate, potassium chloride and other inorganic salts in the atorvastatin mother nucleus M4 (namely a compound VI) crude product 1 in the pulping process, and meanwhile, the pH value of a reaction system is adjusted by adopting a reaction kettle system with a DCS control function, so that the target product M4 can be effectively inhibited from being damaged under acid-base conditions, the generation of unknown impurities (RRT1.15) is reduced, and the refining qualified rate is improved.
2. The refining method adopts reaction kettles with the same volume for pulping and recrystallization, and the adopted mixed solvent can improve the feeding amount of crude products and the output amount of fine products in a single batch, thereby improving the yield and the productivity.
3. The setting of the mixture ratio of the mixed solvent in the recrystallization process and the accurate control of the recovery amount of the mixed solvent not only effectively remove related impurities, but also ensure the refining yield to be more than 95 percent on the premise of ensuring the product quality.
4. The method has the advantages of simple post-treatment, high yield, reutilization of recovered solvent and crystallization mother liquor, suitability for industrial production, high chemical purity of the obtained product, low impurity content, high melting point, short melting range, good stability and high refining yield.
5. The process disclosed by the invention has a high impurity removal rate, wherein the removal rate of the impurity II (defluorinated impurity) is more than 70%, the removal rates of the impurity III (M-fluorine impurity), the impurity I (o-fluorine impurity), the impurity IV (compound III) and the impurity V (dibromo impurity of the compound III) are all more than 85%, the reduction rate of the unknown impurity (RRT1.15) is more than 90%, and the atorvastatin mother nucleus M4 refined product with high purity can be obtained.
Drawings
FIG. 1 is a schematic structural diagram of a DCS reaction kettle system capable of regulating and controlling pH value according to embodiment 1 of the invention.
Detailed Description
The technical solutions of the present application are described below clearly and completely with reference to the following embodiments, and it is obvious that the described embodiments are only a part of the embodiments of the present application, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present application.
Example 1
In the process of refining the crude atorvastatin mother nucleus M4 product, hydrochloric acid or glacial acetic acid is required to be added to adjust the pH value of a reaction system, and the addition amount of the hydrochloric acid or the glacial acetic acid is required to be accurately controlled, in this embodiment, a DCS (distributed control system) reaction kettle system capable of adjusting the pH value is adopted to adjust the pH value, as shown in fig. 1, the DCS reaction kettle system capable of adjusting the pH value comprises a reaction kettle 1, a first adding tank 2, a second adding tank 4 and DCS control equipment;
the first adding tank 2 is filled with hydrochloric acid, and the second adding tank 4 is filled with glacial acetic acid;
a stirring shaft and a stirring paddle are arranged in the reaction kettle 1, a first feeding port and a second feeding port are arranged on the top cover of the reaction kettle 1, the output end of the first adding tank 2 is communicated with the first feeding port on the top cover of the reaction kettle 1 through a first feeding pipe 11, and the output end of the second adding tank 4 is communicated with the second feeding port on the top cover of the reaction kettle 1 through a second feeding pipe 41;
a top cover of the reaction kettle 1 is also provided with a pH meter 5 with a signal transmission module, and the measuring end of the pH meter 5 extends into the reaction kettle 1;
the DCS control equipment comprises a DCS control module 3, the model of the DCS control module 3 is 6XV1830-0EH10, and a computing unit is arranged in the DCS control module 3.
The signal output end of the pH meter 5 is communicated with the signal input end of a DCS control module 3 in the DCS control equipment;
a first electric control valve 12 is arranged on the first feeding pipe 11, a second electric control valve 42 is arranged on the second feeding pipe 41, two branches are arranged at the signal output end of the DCS control module 3, the first branch is communicated with the signal input end of the first electric control valve 12, and the second branch is communicated with the signal input end of the second electric control valve 42;
the first feeding pipe 11 is further provided with a first control valve 13, and the second feeding pipe 41 is further provided with a second control valve 43.
The pH meter 5 with the signal transmission module is Z-PH 100M.
The first electronic control valve 12 and the second electronic control valve 42 are of the type AOX-Q-050.
Before reaction, setting two groups of pH range values according to hydrochloric acid or glacial acetic acid to be added, wherein the value of the pH range value of the first group is 5.60-6.40, the value of the pH range value of the first group is a range to be regulated and controlled when hydrochloric acid is added, the value of the pH range value of the second group is 5.70-5.80, and the value of the pH range value of the second group is a range to be regulated and controlled when glacial acetic acid is added;
in the reaction process, when the pH value of the added hydrochloric acid needs to be regulated, the second control valve 43 is closed, the first control valve 13 is opened, the pH value of the reaction kettle 1 is measured through the measuring end of the pH meter 5, the pH value signal is transmitted to the signal input end of the DCS control module 3 through the signal output end, the DCS control module 3 judges whether the pH value signal is in the set pH range value through the calculating unit, when the pH value in the reaction kettle 1 is larger than the set pH range value, the signal output end of the DCS control module 3 sends an opening signal to the signal input end of the first electric control valve 12, the first electric control valve 12 is opened, the hydrochloric acid is added into the reaction kettle 1 from the first adding tank 2 at the moment, when the pH value in the reaction kettle 1 is smaller than the set pH range value, the signal output end of the DCS control module 3 sends a closing signal to the signal input end of the first electric control valve 12, the first electronically controlled valve 12 is closed.
When the pH value of glacial acetic acid needs to be regulated, the first control valve 13 is closed, the second control valve 43 is opened, the pH value of the reaction kettle 1 is measured through the measuring end of the pH meter 5, the pH value signal is transmitted to the signal input end of the DCS control module 3 through the signal output end, the DCS control module 3 judges whether the pH value signal is within the set pH range value through the calculating unit, when the pH value in the reaction kettle 1 is greater than the set pH range value, the signal output end of the DCS control module 3 sends an opening signal to the signal input end of the second electric control valve 42, the second electric control valve 42 is opened, glacial acetic acid is added into the reaction kettle 1 from the second adding tank 4, when the pH value in the reaction kettle 1 is less than the set pH range value, the signal output end of the DCS control module 3 sends a closing signal to the signal input end of the second electric control valve 42, the second electronically controlled valve 42 is closed.
The connection relationship between the DCS control equipment and other parts in the reaction kettle system with the DCS control function in the invention can be realized by adopting the prior art, which is not the invention point of the invention, so that the description is omitted.
The following examples 2-5 were refined using the crude atorvastatin mother nucleus M4 synthesized by the synthetic route and process described in the background as the starting material.
The detection method in the embodiment comprises the following steps: HPLC detection (chromatographic conditions: workstation: Shimadzu chromatography workstation detector: VWD column temperature: 40 ℃ detection wavelength: 250nm chromatography column: Agilent Eclipse XDB-C18250 mm X4.6 mm X5 μ M (or equivalent) mobile phase is methanol: buffer at a volume ratio of 60:40, the buffer is phosphate-sodium dihydrogen phosphate buffer (0.025M, pH3.0 + -0.05 adjusted with phosphoric acid) flow rate: 1.0ml/min running program: isocratic running time: 60min solvent: mobile phase sample concentration: 0.4mg/ml sample intake: 15 μ l).
The unknown impurity RRT1.15 is an impurity which appears when the ratio of the peak-out time of the impurity to the peak-out time of the main peak is 1.15 under the HPLC detection condition, and is called as the unknown impurity RRT1.15 due to the unknown structure.
Example 2
A refining method of atorvastatin mother nucleus M4 comprises the following specific steps;
(1) adding 1600kg of atorvastatin mother nucleus M4 (namely compound VI) crude product 1 into a reaction kettle with the volume of 5000L, adding 4800kg of water, stirring and mixing, dropwise adding hydrochloric acid to adjust the pH value, controlling the dropwise adding amount of the hydrochloric acid by using a DCS control reaction kettle system capable of regulating and controlling the pH value in the embodiment 1, setting the pH value interval to be 5.60-6.40, opening a first electric control valve 12 for dropwise adding of the hydrochloric acid when the pH value is greater than the interval value, closing the first electric control valve 12 when the pH value is 5.95, and stopping dropwise adding;
then pulping for 2 hours at room temperature, centrifuging, drying under reduced pressure, controlling the water content to be less than or equal to 1 percent, obtaining 1486kg of atorvastatin mother nucleus M4 crude product 2, and detecting by HPLC, wherein the content of atorvastatin mother nucleus M4 in the crude product 2 is 98.95 percent, the water content is 0.027 percent, and the content of each impurity is as follows: 0.085 percent of impurity II (defluorinated impurity), 0.03 percent of impurity III (m-fluorine impurity), 0.010 percent of impurity I (o-fluorine impurity), 0.01 percent of impurity IV (compound III), 0.22 percent of impurity V (dibromo impurity of compound III) and 0.025 percent of unknown impurity RRT 1.15;
(2) sequentially adding the whole batch of atorvastatin mother nucleus M4 crude product 2 and 4950kg of mixed solvent obtained in the step (1) into a 5000L reaction kettle, dissolving, dropwise adding glacial acetic acid to adjust the pH value, controlling the dropwise adding amount of the glacial acetic acid by using a DCS control reaction kettle system capable of adjusting and controlling the pH value in the embodiment 1, setting the pH value interval to be 5.70-5.80, opening a second electric control valve 42 to dropwise add hydrochloric acid when the pH value is greater than the interval value, closing the second electric control valve 42 and stopping dropwise adding when the pH value is 5.75; the mixed solvent is a mixed solvent of methanol and dichloromethane, wherein the mass fraction of the methanol is 45%;
then carrying out hot reflux for 1 hour at the temperature of 40-50 ℃, carrying out suction filtration while the solution is hot, concentrating the filtrate at the temperature of 65 ℃ under normal pressure, recovering 2900kg of the mixed solvent, cooling the concentrated solution to 0-5 ℃, carrying out heat preservation and crystallization for 1 hour, centrifuging, and drying at the temperature of 60 ℃ under reduced pressure (the vacuum degree is 0.09MPa) for 5 hours to obtain 1434kg of refined compound VI (atorvastatin mother nucleus M4);
by taking atorvastatin mother nucleus M4 crude product 2 as a reference, the weight yield of a refined product is 96.52%, through detection, the content of atorvastatin mother nucleus M4 is 99.90%, the content of impurity di (defluorinated impurity) is 0.017%, the impurity tri (M-fluorine impurity), impurity mono (o-fluorine impurity), impurity penta (dibromo impurity of compound III) and impurity penta (dibromo impurity of compound III) are not detected, the content of unknown impurity RRT1.15 is 0.0015%, and the melting point is 202.2-203.5 ℃.
Example 3
A refining method of atorvastatin mother nucleus M4 comprises the following specific steps;
(1) adding 1600kg of atorvastatin mother nucleus M4 (namely compound VI) crude product 1 into a reaction kettle with the volume of 5000L, adding 4800kg of water, stirring and mixing, dropwise adding hydrochloric acid to adjust the pH value, controlling the dropwise adding amount of the hydrochloric acid by using a DCS control reaction kettle system capable of regulating and controlling the pH value in the embodiment 1, setting the pH value interval to be 5.60-6.40, opening a first electric control valve 12 for dropwise adding of the hydrochloric acid when the pH value is greater than the interval value, closing the first electric control valve 12 when the pH value is 6.10, and stopping dropwise adding;
pulping for 2 hours at room temperature, centrifuging, drying under reduced pressure, controlling the water content to be less than or equal to 1 percent to obtain 1481kg of atorvastatin mother nucleus M4 crude product 2, and detecting by HPLC, wherein the content of atorvastatin mother nucleus M4 in the crude product 2 is 99.15 percent, the water content is 0.023 percent, and the content of each impurity is as follows: 0.055% of impurity II (defluorinated impurity), 0.03% of impurity III (m-fluorine impurity), 0.010% of impurity I (o-fluorine impurity), 0.01% of impurity IV (compound III), 0.20% of impurity V (dibromo impurity of compound III), and 0.020% of unknown impurity RRT 1.15;
(2) sequentially adding the whole batch of atorvastatin mother nucleus M4 crude product 2 and 4950kg of mixed solvent obtained in the step (1) into a 5000L reaction kettle, dissolving, dropwise adding glacial acetic acid to adjust the pH value, controlling the dropwise adding amount of the glacial acetic acid by using a DCS control reaction kettle system capable of adjusting and controlling the pH value in the embodiment 1, setting the pH value interval to be 5.70-5.80, opening a second electric control valve 42 to dropwise add hydrochloric acid when the pH value is greater than the interval value, closing the second electric control valve 42 and stopping dropwise adding when the pH value is 5.75; the mixed solvent is a mixed solvent of methanol and dichloromethane, wherein the mass fraction of the methanol is 45%;
then carrying out hot reflux for 1 hour at the temperature of 40-50 ℃, carrying out suction filtration while the solution is hot, concentrating the filtrate at the temperature of 65 ℃ under normal pressure, recovering 2960kg of the mixed solvent, cooling the concentrated solution to 0-5 ℃, carrying out heat preservation crystallization for 1 hour, centrifuging, and drying at the temperature of 60 ℃ under reduced pressure (the vacuum degree is 0.09MPa) for 5 hours to obtain 1423kg of refined compound VI (atorvastatin mother nucleus M4);
by taking atorvastatin mother nucleus M4 crude product 2 as a reference, the weight yield of a refined product is 96.09%, and through detection, the content of atorvastatin mother nucleus M4 is 99.93%, the content of impurity di (defluorinated impurity) is 0.023%, the impurity tri (M-fluorine impurity), impurity mono (o-fluorine impurity), impurity penta (dibromo impurity of compound III) and impurity penta (dibromo impurity of compound III) are not detected, and the unknown impurity RRT1.15 is 0.0010%, and the melting point is 202.2-203.5 ℃.
Example 4
A refining method of atorvastatin mother nucleus M4 comprises the following specific steps;
(1) adding 1600kg of atorvastatin mother nucleus M4 (namely compound VI) crude product 1 into a reaction kettle with the volume of 5000L, adding 4800kg of water, stirring and mixing, dropwise adding hydrochloric acid to adjust the pH value, controlling the dropwise adding amount of the hydrochloric acid by using a DCS control reaction kettle system capable of regulating and controlling the pH value in the embodiment 1, setting the pH value interval to be 5.60-6.40, opening a first electric control valve 12 for dropwise adding of the hydrochloric acid when the pH value is greater than the interval value, closing the first electric control valve 12 when the pH value is 6.00, and stopping dropwise adding;
pulping for 2 hours at room temperature, centrifuging, drying under reduced pressure, controlling the water content to be less than or equal to 1 percent to obtain 1482kg of atorvastatin mother nucleus M4 crude product 2, wherein HPLC detection shows that the content of atorvastatin mother nucleus M4 in the crude product 2 is 98.87 percent, the water content is 0.018 percent, and the content of each impurity is as follows: 0.085 percent of impurity II (defluorinated impurity), 0.03 percent of impurity III (m-fluorine impurity), 0.010 percent of impurity I (o-fluorine impurity), 0.01 percent of impurity IV (compound III), 0.23 percent of impurity V (dibromo impurity of compound III), and 0.025 percent of unknown impurity RRT 1.15;
(2) sequentially adding the whole batch of atorvastatin mother nucleus M4 crude product 2 and 4950kg of mixed solvent obtained in the step (1) into a 5000L reaction kettle, dissolving, dropwise adding glacial acetic acid to adjust the pH value, controlling the dropwise adding amount of the glacial acetic acid by using a DCS control reaction kettle system capable of adjusting and controlling the pH value in the embodiment 1, setting the pH value interval to be 5.70-5.80, opening a second electric control valve 42 to dropwise add hydrochloric acid when the pH value is greater than the interval value, closing the second electric control valve 42 and stopping dropwise adding when the pH value is 5.75; the mixed solvent is a mixed solvent of methanol and dichloromethane, wherein the mass fraction of the methanol is 45%;
then carrying out hot reflux for 1 hour at the temperature of 40-50 ℃, carrying out suction filtration while the solution is hot, concentrating the filtrate at the temperature of 65 ℃ under normal pressure, recovering 3000kg of the mixed solvent, cooling the concentrated solution to 5-10 ℃, carrying out heat preservation and crystallization for 1 hour, centrifuging, and drying at the temperature of 65 ℃ under reduced pressure (the vacuum degree is 0.09MPa) for 4 hours to obtain 1401kg of a refined product of the compound VI (atorvastatin mother nucleus M4);
by taking atorvastatin mother nucleus M4 crude product 2 as a reference, the weight yield of a refined product is 95.14%, and through detection, the content of atorvastatin mother nucleus M4 is 99.92%, the content of impurity II (defluorination impurity) is 0.025%, the impurity III (M-fluorine impurity), the impurity I (o-fluorine impurity), the impurity V (dibromo impurity of a compound III) and the impurity V (dibromo impurity of the compound III) are not detected, the unknown impurity RRT1.15 is 0.002%, and the melting point is 202.2-203.5 ℃.
Example 5
A refining method of atorvastatin mother nucleus M4 comprises the following specific steps;
(1) adding 1600kg of atorvastatin mother nucleus M4 (namely compound VI) crude product 1 into a reaction kettle with the volume of 5000L, adding 5000kg of water, stirring and mixing, dropwise adding hydrochloric acid to adjust the pH value, controlling the dropwise adding amount of the hydrochloric acid by using a DCS control reaction kettle system capable of regulating and controlling the pH value in the embodiment 1, setting the pH value interval to be 5.60-6.40, opening a first electric control valve 12 for dropwise adding of the hydrochloric acid when the pH value is greater than the interval value, closing the first electric control valve 12 when the pH value is 6.00, and stopping dropwise adding;
pulping for 2 hours at room temperature, centrifuging, drying under reduced pressure, controlling the water content to be less than or equal to 1 percent to obtain 1485kg of atorvastatin mother nucleus M4 crude product 2, and detecting by HPLC, wherein the content of atorvastatin mother nucleus M4 in the crude product 2 is 99.20 percent, the water content is 0.045 percent, and the content of each impurity is as follows: 0.080% of impurity II (defluorinated impurity), 0.03% of impurity III (m-fluorine impurity), 0.010% of impurity I (o-fluorine impurity), 0.01% of impurity IV (compound III), 0.21% of impurity V (dibromo impurity of compound III), and 0.021% of unknown impurity RRT 1.15;
(2) sequentially adding the whole batch of atorvastatin mother nucleus M4 crude product 2 and 4905kg of mixed solvent in the step (1) into a 5000L reaction kettle, dissolving, dropwise adding glacial acetic acid to adjust the pH value, controlling the dropwise adding amount of the glacial acetic acid by using a DCS control reaction kettle system capable of adjusting and controlling the pH value in the embodiment 1, setting the pH value interval to be 5.70-5.80, opening a second electric control valve 42 to dropwise add hydrochloric acid when the pH value is greater than the interval value, closing the second electric control valve 42 and stopping dropwise adding when the pH value is 5.80; the mixed solvent is a mixed solvent of methanol and dichloromethane, wherein the mass fraction of the methanol is 45%;
then carrying out hot reflux for 1 hour at the temperature of 40-50 ℃, carrying out suction filtration while the solution is hot, concentrating the filtrate at the temperature of 65 ℃ under normal pressure, recovering 2970kg of the mixed solvent, cooling the concentrated solution to 4-7 ℃, carrying out heat preservation crystallization for 1 hour, centrifuging, and drying at the temperature of 65 ℃ under reduced pressure (the vacuum degree is 0.09MPa) for 4 hours to obtain 1415kg of refined compound VI (atorvastatin mother nucleus M4);
by taking atorvastatin mother nucleus M4 crude product 2 as a reference, the weight yield of a refined product is 95.32%, and through detection, the content of atorvastatin mother nucleus M4 is 99.95%, the content of impurity II (defluorinated impurity) is 0.020%, impurity III (M-fluorine impurity), impurity I (o-fluorine impurity), impurity V (dibromo impurity of compound III) and impurity V (dibromo impurity of compound III) are not detected, and the unknown impurity RRT1.15, the content of which is 0.008% and the melting point of which is 202.2-203.5 ℃.
Comparative example 1
The refining step in the comparative example 1 is basically the same as that in the example 2, except that hydrochloric acid is not added in the step (1) to adjust the pH value, pulping is directly carried out, and the finally obtained atorvastatin mother nucleus M4 crude product 2 contains an unknown impurity RRT1.15 with the content of 0.7 percent in addition to the impurity II, the impurity III, the impurity I, the impurity IV and the impurity V through detection; and (3) regulating the pH value without adding glacial acetic acid in the step (2), directly carrying out hot reflux, and detecting that the obtained refined atorvastatin mother nucleus M4 product contains not only impurities but also unknown impurity RRT1.15 with the content of 0.5%.
Compared with the example 2, the comparison example 1 shows that the content of the unknown impurity RRT1.15 can be reduced by accurately regulating and controlling the pH value in the reaction process, so that the purity and the quality of the refined atorvastatin mother nucleus M4 product are improved.
The above examples are illustrative of the present invention, and the present invention is not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents and are included in the scope of the present invention.
Claims (7)
1. A refining method of atorvastatin mother nucleus M4 is characterized by comprising the following steps:
(1) mixing the atorvastatin mother nucleus M4 crude product 1 with water, stirring for dissolving, and adding acid to adjust the pH value to 5.60-6.40; then pulping for 2-3 hours at room temperature, centrifuging and drying to obtain a crude product 2 of atorvastatin mother nucleus M4;
(2) mixing the atorvastatin mother nucleus M4 crude product 2 in the step (1) with a mixed solvent, stirring for dissolving, and adding acid to adjust the pH value to 5.7-5.8; and then carrying out hot reflux for 1-3 hours at the temperature of 35-50 ℃, carrying out suction filtration while the solution is hot, concentrating the filtrate at the temperature of 60-65 ℃ under normal pressure, recovering the mixed solvent, cooling the concentrated solution to 0-10 ℃, carrying out heat preservation and recrystallization for 1-3 hours, centrifuging, and drying to obtain the refined atorvastatin mother nucleus M4.
2. The refining method of claim 1, wherein the mass ratio of the crude atorvastatin mother nucleus M4 product 1 to water in the step (1) is 1: 3.0 to 5.0.
3. The purification method according to claim 1, wherein the pH in the step (1) is adjusted by using an inorganic acid selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.
4. The refining method of claim 1, wherein the mixed solvent in the step (2) is a mixed solvent of methanol and dichloromethane, and the mass fraction of methanol is 40% to 60%.
5. The refining method of claim 1, wherein in the step (2), the mass ratio of the crude atorvastatin mother nucleus M4 2 to the mixed solvent is 1: 3 to 3.5.
6. The purification process according to claim 1, wherein in the step (2), the pH is adjusted by using an organic acid selected from the group consisting of glacial acetic acid, tartaric acid, oxalic acid and propionic acid.
7. The purification process according to claim 1, wherein the amount of the mixed solvent recovered by the atmospheric concentration in the step (2) is 55 to 65% of the original amount of the solvent.
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Citations (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5998633A (en) * | 1996-07-29 | 1999-12-07 | Warner-Lambert Company | Process for the synthesis of protected esters of (S)-3,4-dihydroxybutyric acid |
| CN1299811A (en) * | 2000-12-08 | 2001-06-20 | 中国科学院上海有机化学研究所 | Alpha-alkylacyl-beta-substituted benzoyl-beta-phenylpropionyl aniline and its synthesis and use |
| CN1325844A (en) * | 2000-05-31 | 2001-12-12 | 中国医学科学院药物研究所 | Process for synthesizing (+/-)p-fluoro-2(2-methyl-propionyl)-4-oxy-N,3-diphenyl-phenylbutylamide |
| WO2003004457A2 (en) * | 2001-07-04 | 2003-01-16 | Ciba Specialty Chemicals Holding Inc. | Preparation process for atorvastatin and intermediates |
| WO2004103957A1 (en) * | 2003-05-22 | 2004-12-02 | Biocon Limited | Novel dithioketal |
| WO2004108660A1 (en) * | 2003-06-09 | 2004-12-16 | Biocon Limited | Novel halo-substituted active methylene compounds |
| US20070249865A1 (en) * | 2004-08-26 | 2007-10-25 | Biocon Limited | Process for Preparation of 4-Fluoro-Alpha-[2-Methyl-1-Oxopropyl]-Gamma-Oxo-N-Beta- Diphenylbenzene Butane Amide |
| US20080280971A1 (en) * | 2007-05-08 | 2008-11-13 | Protia, Llc | Deuterium-enriched atorvastatin |
| US20090221852A1 (en) * | 2005-09-09 | 2009-09-03 | Pfizer Inc. | Preparation of an Atorvastatin Intermediate |
| US20090298907A1 (en) * | 2008-05-29 | 2009-12-03 | Pai Ganesh Gurpur | METHOD FOR THE PREPARATION OF 4-FLUORO-ALPHA-[2-METHYL-1-OXOPROPYL]-y-OXO-N-BETA-DIPHENYLBENZENEBUTANAMIDE AND PRODUCTS THEREFROM |
| CN101805279A (en) * | 2010-01-22 | 2010-08-18 | 绍兴民生医药有限公司 | Preparation method of atorvastatin calcium |
| US20110118476A1 (en) * | 2007-08-03 | 2011-05-19 | Pfizer Inc. | Process for Preparing Chiral Compounds |
| US20110263870A1 (en) * | 2010-04-23 | 2011-10-27 | Helvetica Industries (P) Limited | Novel pyrrole derivatives and their synthesis |
| CN102702014A (en) * | 2012-05-28 | 2012-10-03 | 扬子江药业集团江苏海慈生物药业有限公司 | Method for preparing atorvastatin calcium intermediate |
| WO2012145808A1 (en) * | 2011-04-25 | 2012-11-01 | Universidade Estadual De Campinas - Unicamp | Method for preparing atorvastatin calcium using new intermediates and resulting atorvastatin |
| US20130184493A1 (en) * | 2011-04-21 | 2013-07-18 | Vijayasri Organics Limited | PROCESS FOR PREPARATION OF 4-FLUORO-alpha-[2METHYL-L-OXOPROPYL]-gamma-OXO-N-beta-DIPHENYLBENZENE BUTANE AMIDE |
| CN109836350A (en) * | 2017-11-28 | 2019-06-04 | 江苏暨明医药科技有限公司 | The environment-friendly preparation method of Atorvastatin key intermediate |
| WO2020016903A1 (en) * | 2018-07-18 | 2020-01-23 | Arch Pharmalabs Limited | An improved and commercially viable process for preparation of pyrrole derivatives with improved impurity profile & minimisation of unit operations. |
| CN111909048A (en) * | 2020-09-07 | 2020-11-10 | 浙江宏元药业股份有限公司 | Method for synthesizing atorvastatin calcium intermediate by multi-component one-pot method |
| CN113788766A (en) * | 2021-10-20 | 2021-12-14 | 宿迁盛基医药科技有限公司 | Preparation method of atorvastatin calcium intermediate |
| CN113816867A (en) * | 2021-10-20 | 2021-12-21 | 宿迁盛基医药科技有限公司 | Method for preparing atorvastatin calcium intermediate by using continuous flow tubular reactor |
-
2021
- 2021-12-31 CN CN202111659985.5A patent/CN114195670B/en active Active
Patent Citations (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5998633A (en) * | 1996-07-29 | 1999-12-07 | Warner-Lambert Company | Process for the synthesis of protected esters of (S)-3,4-dihydroxybutyric acid |
| CN1325844A (en) * | 2000-05-31 | 2001-12-12 | 中国医学科学院药物研究所 | Process for synthesizing (+/-)p-fluoro-2(2-methyl-propionyl)-4-oxy-N,3-diphenyl-phenylbutylamide |
| CN1299811A (en) * | 2000-12-08 | 2001-06-20 | 中国科学院上海有机化学研究所 | Alpha-alkylacyl-beta-substituted benzoyl-beta-phenylpropionyl aniline and its synthesis and use |
| WO2003004457A2 (en) * | 2001-07-04 | 2003-01-16 | Ciba Specialty Chemicals Holding Inc. | Preparation process for atorvastatin and intermediates |
| WO2004103957A1 (en) * | 2003-05-22 | 2004-12-02 | Biocon Limited | Novel dithioketal |
| WO2004108660A1 (en) * | 2003-06-09 | 2004-12-16 | Biocon Limited | Novel halo-substituted active methylene compounds |
| US20070249865A1 (en) * | 2004-08-26 | 2007-10-25 | Biocon Limited | Process for Preparation of 4-Fluoro-Alpha-[2-Methyl-1-Oxopropyl]-Gamma-Oxo-N-Beta- Diphenylbenzene Butane Amide |
| US20090221852A1 (en) * | 2005-09-09 | 2009-09-03 | Pfizer Inc. | Preparation of an Atorvastatin Intermediate |
| US20080280971A1 (en) * | 2007-05-08 | 2008-11-13 | Protia, Llc | Deuterium-enriched atorvastatin |
| US20110118476A1 (en) * | 2007-08-03 | 2011-05-19 | Pfizer Inc. | Process for Preparing Chiral Compounds |
| US20090298907A1 (en) * | 2008-05-29 | 2009-12-03 | Pai Ganesh Gurpur | METHOD FOR THE PREPARATION OF 4-FLUORO-ALPHA-[2-METHYL-1-OXOPROPYL]-y-OXO-N-BETA-DIPHENYLBENZENEBUTANAMIDE AND PRODUCTS THEREFROM |
| CN101805279A (en) * | 2010-01-22 | 2010-08-18 | 绍兴民生医药有限公司 | Preparation method of atorvastatin calcium |
| US20110263870A1 (en) * | 2010-04-23 | 2011-10-27 | Helvetica Industries (P) Limited | Novel pyrrole derivatives and their synthesis |
| US20130184493A1 (en) * | 2011-04-21 | 2013-07-18 | Vijayasri Organics Limited | PROCESS FOR PREPARATION OF 4-FLUORO-alpha-[2METHYL-L-OXOPROPYL]-gamma-OXO-N-beta-DIPHENYLBENZENE BUTANE AMIDE |
| WO2012145808A1 (en) * | 2011-04-25 | 2012-11-01 | Universidade Estadual De Campinas - Unicamp | Method for preparing atorvastatin calcium using new intermediates and resulting atorvastatin |
| CN102702014A (en) * | 2012-05-28 | 2012-10-03 | 扬子江药业集团江苏海慈生物药业有限公司 | Method for preparing atorvastatin calcium intermediate |
| CN109836350A (en) * | 2017-11-28 | 2019-06-04 | 江苏暨明医药科技有限公司 | The environment-friendly preparation method of Atorvastatin key intermediate |
| WO2020016903A1 (en) * | 2018-07-18 | 2020-01-23 | Arch Pharmalabs Limited | An improved and commercially viable process for preparation of pyrrole derivatives with improved impurity profile & minimisation of unit operations. |
| CN111909048A (en) * | 2020-09-07 | 2020-11-10 | 浙江宏元药业股份有限公司 | Method for synthesizing atorvastatin calcium intermediate by multi-component one-pot method |
| CN113788766A (en) * | 2021-10-20 | 2021-12-14 | 宿迁盛基医药科技有限公司 | Preparation method of atorvastatin calcium intermediate |
| CN113816867A (en) * | 2021-10-20 | 2021-12-21 | 宿迁盛基医药科技有限公司 | Method for preparing atorvastatin calcium intermediate by using continuous flow tubular reactor |
Non-Patent Citations (4)
| Title |
|---|
| RAJESHWAR REDDY SAGYAM ET AL.: "An Efficient Synthesis of Highly Substituted Pyrrole and Bis Pyrrole Derivatives", 《J. HETEROCYCLIC CHEM.》, vol. 2018, pages 923 - 926 * |
| 范朋高 等: "4-氟-α-（2-甲基-1-氧丙基）-γ-氧-N, β-二苯基-苯丁酰胺的合成", 《中国药物化学杂志》, vol. 15, no. 1, pages 48 - 50 * |
| 邢玉芝 等: "阿托伐他汀钙母核的合成及工艺研究", 《中国优秀硕士学位论文全文数据库 工程科技I辑》, pages 1 - 68 * |
| 饶历 等: "阿托伐他汀钙中间体的合成工艺研究", 《武汉工程大学学报》, vol. 32, no. 12, pages 10 - 12 * |
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