CN114195670B - Refining method of atorvastatin mother nucleus M4 - Google Patents
Refining method of atorvastatin mother nucleus M4 Download PDFInfo
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- CN114195670B CN114195670B CN202111659985.5A CN202111659985A CN114195670B CN 114195670 B CN114195670 B CN 114195670B CN 202111659985 A CN202111659985 A CN 202111659985A CN 114195670 B CN114195670 B CN 114195670B
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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 77
- 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 77
- 229960005370 atorvastatin Drugs 0.000 title claims abstract description 77
- 238000000034 method Methods 0.000 title claims abstract description 45
- 238000007670 refining Methods 0.000 title claims abstract description 31
- 239000012043 crude product Substances 0.000 claims abstract description 35
- 239000012046 mixed solvent Substances 0.000 claims abstract description 34
- 239000000047 product Substances 0.000 claims abstract description 18
- 238000004537 pulping Methods 0.000 claims abstract description 9
- 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 56
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 40
- 229960000583 acetic acid Drugs 0.000 claims description 20
- 239000012362 glacial acetic acid Substances 0.000 claims description 20
- 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
- 238000003756 stirring Methods 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 11
- 239000000706 filtrate Substances 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 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
- 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
- 238000010992 reflux Methods 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
- 238000001816 cooling Methods 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 238000004321 preservation Methods 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- 238000000746 purification Methods 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
- 238000000967 suction filtration Methods 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 123
- 238000006243 chemical reaction Methods 0.000 abstract description 52
- 230000008569 process Effects 0.000 abstract description 18
- 230000001105 regulatory effect Effects 0.000 abstract description 15
- 150000001875 compounds Chemical class 0.000 abstract description 12
- 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
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 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
- 238000002425 crystallisation Methods 0.000 abstract description 3
- 230000008025 crystallization Effects 0.000 abstract description 3
- 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
- 238000012797 qualification Methods 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
- 238000004064 recycling Methods 0.000 abstract description 2
- 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
- 230000001276 controlling effect Effects 0.000 description 17
- 239000000203 mixture Substances 0.000 description 17
- 125000000950 dibromo group Chemical group Br* 0.000 description 13
- 238000001514 detection method Methods 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 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 4
- 230000008054 signal transmission Effects 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 3
- 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
- 230000000694 effects Effects 0.000 description 2
- 238000011049 filling Methods 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
- 230000009467 reduction Effects 0.000 description 2
- 238000006467 substitution reaction 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
- -1 2-methyl-1-oxopropyl Chemical group 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
- 238000010009 beating Methods 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
- 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
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- DFIWJEVKLWMZBI-UHFFFAOYSA-M sodium;dihydrogen phosphate;phosphoric acid Chemical compound [Na+].OP(O)(O)=O.OP(O)([O-])=O DFIWJEVKLWMZBI-UHFFFAOYSA-M 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
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 an atorvastatin mother nucleus M4. According to the invention, the pH value of the system is regulated by adopting the DCS reaction kettle system, so that the target product M4 can be effectively inhibited from being damaged under the acid-base condition, the generation of unknown impurities is reduced, and the refining qualification rate is improved. According to the method, inorganic salts such as potassium carbonate, potassium bicarbonate and potassium chloride in the crude product 1 of the atorvastatin mother nucleus M4 (namely the compound VI) synthesized by a converging method can be removed in the pulping process, and the mixed solvent is utilized in the recrystallization process, so that impurities are effectively removed and reduced, and the refining yield is improved. The method has the advantages of simple post-treatment, high productivity, recycling of the recovered solvent and the crystallization mother liquor, suitability for industrial production, high chemical purity, low impurity content, high melting point, short melting range and good stability of the obtained product.
Description
Technical Field
The invention belongs to the technical field of drug synthesis processes, and particularly relates to a refining method of an atorvastatin mother nucleus M4.
Background
Atorvastatin calcium is a statin hypolipidemic drug commonly developed by the company Warnerlambert and Prizer in the United states, and can effectively inhibit the activity of hydroxymethylglutaryl-CoA (HMKG-CoA) reductase and obviously reduce the content of total cholesterol and low-density lipoprotein cholesterol. The traditional Chinese medicine composition has the advantages of small toxic and side effects, unique action mechanism, good tolerance and very broad market application prospect.
Atorvastatin mother nucleus M4 is a mother ring intermediate for synthesizing atorvastatin calcium, and the molecular formula is C 26 H 24 FNO 3 The chemical name is: 4-fluoro-alpha- [ 2-methyl-1-oxopropyl group]- γ -oxo-N, β -diphenylphenylbutyramide having the structural formula:
the preparation method of atorvastatin mother M4 is mainly divided into two types: linear synthesis and convergent synthesis. Compared with the two, the convergent synthesis method has the advantages of easy quality control, simple and easy operation, easy separation and purification of target products, economy and practicability, and is a main stream synthesis route for synthesizing the atorvastatin mother nucleus M4 at present.
In the prior art, a plurality of reports are about the preparation process of the atorvastatin mother nucleus M4, but the refining process is described freshly. The atorvastatin mother core M4 contains a plurality of functional groups, the pH value is relatively clear, in the process of purifying the atorvastatin mother core M4, new unknown impurities can be generated due to the difference of the pH values, and the atorvastatin mother core M4 is difficult to effectively remove, so that the melting point of an M4 product is unqualified. Through a great deal of experimental study, the impurity generated in the process of synthesizing the atorvastatin mother nucleus M4 is closely related to the pH value and the moisture in the system. How to purify atorvastatin mother M4 and improve the yield and purity is a technical problem to be solved urgently.
In the prior art, the synthesis route of the atorvastatin mother M4 is as follows:
the method comprises the following specific steps: 1) The benzene acetyl chloride and fluorobenzene undergo a Friedel-crafts reaction under the condition of Lewis acid to obtain a compound II; 2) Brominating the compound II to obtain a compound III; 3) Methyl isobutyrylacetate (compound IV) is reacted with aniline to give amidate V; 4) Synthesizing a compound VI (atorvastatin mother M4) from a compound V and a compound III in an alkaline environment; wherein, in the step 4), potassium carbonate is used for providing an alkaline environment, and alkaline inorganic salts such as potassium carbonate, potassium bicarbonate, potassium bromide and the like are coated in the compound VI in the reaction process.
Meanwhile, a plurality of impurities can be generated in the process of preparing the compound VI by using the synthetic route, and the main impurity components are as follows:
wherein, the fifth impurity is generated when excessive bromine is dripped in the bromination procedure in the step 2); impurities one to four are produced in step 4). In order to obtain high-quality atorvastatin mother M4, relevant impurities (impurities one to five) in the synthesis process are effectively removed, and the crude product of the atorvastatin mother M4 needs to be refined.
Meanwhile, research and development personnel analyze and display unknown impurities (RRT 1.15) through an HPLC method in the refining process of the atorvastatin mother nucleus M4 crude product, the impurities are difficult to remove after being generated, the quality of a final product is directly influenced, the melting point is unqualified in the product detection process, the one-time refining qualification rate of the product is low, and the like, the subsequent reworking treatment is needed, the production efficiency is directly influenced, and the product cost is increased.
In order to improve single batch yield and productivity, the invention adopts a mixed solvent method to refine the crude product of the 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 productivity are improved by improving the feeding quantity 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 (impurities one to five) in the crude atorvastatin mother nucleus M4 are effectively removed, and meanwhile, unknown impurities (RRT 1.15) are prevented from being generated in the refining process.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
a refining method of atorvastatin mother nucleus M4 comprises the following steps:
(1) Mixing the crude product 1 of the atorvastatin mother nucleus M4 (namely a compound VI) with water, stirring for dissolving, and adding acid to adjust the pH value to 5.60-6.40; pulping for 2-3 hours at room temperature, centrifuging, and drying to obtain crude atorvastatin mother nucleus M4 2;
(2) Mixing the crude product 2 of the atorvastatin mother nucleus M4 in the step (1) with a mixed solvent, stirring for dissolution, 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 filtrate is hot, concentrating the filtrate at normal pressure at the temperature of 60-65 ℃, 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 crude product 1 of the atorvastatin mother M4 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 to 6.15.
Further, in the step (1), the water content is dried to be less than or equal to 1%.
Furthermore, in the step (2), a mixed solvent is added as a recrystallization solvent to recrystallize the crude product 2 of the atorvastatin mother nucleus M4.
Further, in the step (2), the mixed solvent 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 crude product 2 of the atorvastatin mother nucleus M4 to the mixed solvent is 1:3 to 3.5, the volume ratio is 1:2 to 2.5.
In the step (2), the pH value is adjusted by adopting organic acid, wherein the organic acid is glacial acetic acid, tartaric acid, oxalic acid or propionic acid.
Further preferably, glacial acetic acid is used to adjust the pH to 5.75.
Further, the amount of the solvent recovered by normal pressure concentration in the step (2) is 55 to 65 percent of the amount of the original solvent.
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 in the process of refining the crude atorvastatin mother nucleus M4 to adjust the pH value of a reaction system, and the addition amount of the acid is required 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 first feeding hole and a second feeding hole are formed in the top cover of the reaction kettle, the output end of the first feeding tank is communicated with the first feeding hole in 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 hole in the top cover of the reaction kettle through a second feeding pipe;
the top cover of the reaction kettle is also provided with a pH meter with a signal transmission module, and the measuring end of the pH meter extends into the reaction kettle;
the DCS control equipment comprises a DCS control module, a calculation unit is arranged in the DCS control module, and a signal output end of the pH meter is communicated with a 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 automatically controlled valve of second 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.
Further, the first feeding pipe is further provided with a first control valve, and the second feeding pipe is further provided with a second control valve.
Further, the model of the pH meter with the signal transmission module is Z-PH100M.
Further, the model of the first electric control valve and the second electric control valve is AOX-Q-050.
Specifically, the DCS control device of the present invention may be a common device in the prior art, and the structure and the components of the DCS control device are not the points of the present invention, so that the description thereof will not be repeated.
Compared with the prior art, the invention has the beneficial effects that:
1. according to the refining method of the crude atorvastatin mother nucleus M4, inorganic salts such as potassium carbonate, potassium bicarbonate and potassium chloride in the crude atorvastatin mother nucleus M4 (namely a compound VI) 1 can be removed in the pulping process, meanwhile, the pH value of a reaction system is regulated 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 the acid-base condition, the generation of unknown impurities (RRT 1.15) is reduced, and the refining qualification rate is improved.
2. The refining method adopts the reaction kettle with the same volume to carry out beating and recrystallization, the mixed solvent adopted can improve the feeding amount of single batch crude products and the junction amount of fine products, thereby improving the yield and the productivity, the single batch yield of the reaction kettle with the volume of 5000L can reach more than 1400kg, and the monthly productivity can reach 42 tons if the refining is carried out for 1 batch per day through calculation.
3. The setting of the mixed solvent ratio 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 that the refined yield reaches more than 95 percent on the premise of ensuring the product quality.
4. The method has the advantages of simple post-treatment, high productivity, recycling of the recovered solvent and the 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 has high impurity removal rate, wherein the impurity removal rate of the impurity II (defluorinated impurity) is more than 70%, the impurity III (M-fluoro impurity), the impurity I (o-fluoro impurity), the impurity IV (compound III) and the impurity V (dibromo impurity of compound III) are all more than 85%, the reduction rate of the unknown impurity (RRT 1.15) is more than 90%, and the atorvastatin mother nucleus M4 fine product with higher purity can be obtained.
Drawings
FIG. 1 is a schematic structural diagram of a DCS reactor system capable of adjusting and controlling pH according to embodiment 1 of the present invention.
Detailed Description
The following description of the embodiments of the present application will be made clearly and fully with reference to the accompanying drawings, in which it is evident that the embodiments described are only some, but not all, of the embodiments of the present application. All other embodiments, which can be made by one of ordinary skill in the art without undue burden from the present disclosure, are within the scope of the present disclosure.
Example 1
In the process of refining the crude atorvastatin mother nucleus M4, 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 reaction kettle system capable of adjusting and controlling the pH value is adopted to adjust and control the pH value, as shown in fig. 1, and 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 hole and a second feeding hole are formed in the top cover of the reaction kettle 1, the output end of the first feeding tank 2 is communicated with the first feeding hole in the top cover of the reaction kettle 1 through a first feeding pipe 11, and the output end of the second feeding tank 4 is communicated with the second feeding hole in the top cover of the reaction kettle 1 through a second feeding pipe 41;
the 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 stretches into the reaction kettle 1;
the DCS control equipment comprises a DCS control module 3, the model number of the DCS control module 3 is 6XV1830-0EH10, a computing unit is arranged in the DCS control module 3, and particularly, the DCS control equipment is common equipment in the prior art, and the structure and the component parts of the DCS control equipment are not the points of the invention, so that the description is omitted.
The signal output end of the pH meter 5 is communicated with the signal input end of the DCS control module 3 in the DCS control equipment;
the first charging pipe 11 is provided with a first electric control valve 12, the second charging pipe 41 is provided with a second electric control valve 42, the signal output end of the DCS control module 3 is provided with two branches, 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 model of the pH meter 5 with the signal transmission module is Z-PH100M.
The first electrically controlled valve 12 and the second electrically controlled valve 42 are of the type AOX-Q-050.
Before the reaction, setting two groups of pH range values according to hydrochloric acid or glacial acetic acid to be added, wherein the value of the first group of pH range values is between 5.60 and 6.40, the value of the first group of pH range values is a range needing to be regulated when hydrochloric acid is added, the value of the second group of pH range values is between 5.70 and 5.80, and the value of the second group of pH range values is a range needing to be regulated when glacial acetic acid is added;
in the reaction process, when the pH value of the added hydrochloric acid is required to be regulated and controlled, the second control valve 43 is closed first, 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, a 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 a set pH range through the calculating unit, when the pH value in the reaction kettle 1 is greater than the set pH range, 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, 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, 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, and the first electric control valve 12 is closed.
When the pH value of glacial acetic acid is required to be regulated and controlled, 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, a 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 a 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 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 at the moment, and 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 second electric control valve 42, and the second electric control valve 42 is closed.
In the invention, the connection relation between the DCS control equipment and other components in the reaction kettle system with the DCS control function is only needed by adopting the prior art, and is not the point of the invention, so that the description is omitted.
Examples 2 to 5 below were refined using crude atorvastatin mother M4 synthesized by the synthetic route and process described in the background art as raw materials.
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-C18 mm. Times.4.6 mm. Times.5 μm (or equivalent) mobile phase: methanol: buffer in a volume ratio of 60:40, the buffer being sodium phosphate-dihydrogen phosphate buffer (0.025M, pH 3.0.+ -. 0.05 adjusted with phosphoric acid) flow rate: 1.0ml/min run program: isocratic run duration: 60min solvent: mobile phase sample concentration: 0.4mg/ml sample introduction amount: 15. Mu.l).
The unknown impurity RRT1.15 is an impurity which appears when the ratio of the peak time of the impurity to the peak time of the main peak is 1.15 under the condition of HPLC detection, and is called as the unknown impurity RRT1.15 because the structure is unknown.
Example 2
A refining method of atorvastatin mother nucleus M4 comprises the following specific steps;
(1) Adding 1600kg of atorvastatin mother nucleus M4 (namely a 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 hydrochloric acid by a DCS control reaction kettle system capable of regulating 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 to carry out hydrochloric acid dropwise adding when the pH value is larger than the interval value, closing the first electric control valve 12 when the pH value is 5.95, 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%, obtaining 1486kg of crude product 2 of atorvastatin mother nucleus M4, detecting by HPLC, wherein the content of atorvastatin mother nucleus M4 in the crude product 2 is 98.95%, the water content is 0.027%, and the content of each impurity is as follows: 0.085% of impurity two (defluorinated impurity), 0.03% of impurity three (m-fluoro impurity), 0.010% of impurity one (o-fluoro impurity), 0.01% of impurity four (compound III), 0.22% of impurity five (dibromo impurity of compound III) and 0.025% of unknown impurity RRT 1.15;
(2) Sequentially adding a whole batch of atorvastatin mother nucleus M4 crude products 2 and 4950kg 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 a DCS control reaction kettle system capable of regulating 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 carry out hydrochloric acid dropwise adding when the pH value is greater than the interval value, closing the second electric control valve 42 when the pH value is 5.75, and stopping dropwise adding; the mixed solvent is a mixed solvent of methanol and dichloromethane, wherein the mass fraction of the methanol is 45%;
then, the mixture is refluxed for 1 hour at the temperature of 40 to 50 ℃, filtered while the mixture is hot, the filtrate is concentrated and recycled under normal pressure at the temperature of 65 ℃ to obtain 2900kg of mixed solvent, the concentrated solution is cooled to 0 to 5 ℃, the temperature is kept for 1 hour, the mixture is centrifuged, and the mixture is dried for 5 hours at the temperature of 60 ℃ under reduced pressure (the vacuum degree is 0.09 MPa) to obtain 1434kg of refined atorvastatin mother nucleus M4;
the weight yield of the refined product is 96.52 percent based on the crude product 2 of the atorvastatin mother nucleus M4, the content of the atorvastatin mother nucleus M4 is 99.90 percent, the content of impurity two (defluorinated impurities) is 0.017 percent, the impurity three (M-fluoro impurities), the impurity one (o-fluoro impurities), the impurity five (dibromo impurities of the compound III) and the impurity five (dibromo impurities of the compound III) are not detected, the content of unknown impurity RRT1.15 is 0.0015 percent, 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 a 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 hydrochloric acid by a DCS control reaction kettle system capable of regulating 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 to carry out hydrochloric acid dropwise adding when the pH value is larger 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%, obtaining 1481kg of crude product 2 of atorvastatin mother nucleus M4, detecting by HPLC, wherein the content of atorvastatin mother nucleus M4 in the crude product 2 is 99.15%, the water content is 0.023%, and the content of each impurity is as follows: 0.055% of impurity II (defluorinated impurity), 0.03% of impurity III (m-fluoro impurity), 0.010% of impurity I (o-fluoro impurity), 0.01% of impurity IV (compound III), 0.20% of impurity V (dibromo impurity of compound III), 1.15% of unknown impurity RRT and 0.020%;
(2) Sequentially adding a whole batch of atorvastatin mother nucleus M4 crude products 2 and 4950kg 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 a DCS control reaction kettle system capable of regulating 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 carry out hydrochloric acid dropwise adding when the pH value is greater than the interval value, closing the second electric control valve 42 when the pH value is 5.75, and stopping dropwise adding; the mixed solvent is a mixed solvent of methanol and dichloromethane, wherein the mass fraction of the methanol is 45%;
then, the mixture is heated and refluxed for 1 hour at the temperature of 40 to 50 ℃, and is filtered while the mixture is hot, the filtrate is concentrated and recycled under normal pressure at the temperature of 65 ℃ to 2960kg of mixed solvent, the concentrated solution is cooled to 0 to 5 ℃, the temperature is kept for 1 hour, the mixture is centrifuged, and the mixture is dried for 5 hours at the temperature of 60 ℃ under reduced pressure (the vacuum degree is 0.09 MPa), thus obtaining 1423kg of refined atorvastatin mother nucleus M4;
the weight yield of the refined product is 96.09 percent by taking the crude product 2 of the atorvastatin mother nucleus M4 as a reference, and the content of the atorvastatin mother nucleus M4 is 99.93 percent, the content of the impurity di (defluorinated impurity) is 0.023 percent, the impurity tri (M-fluoro impurity), the impurity mono (o-fluoro impurity), the impurity penta (dibromo impurity of the compound III) and the impurity penta (dibromo impurity of the compound III) are not detected, the unknown impurity RRT is 1.15, the content is 0.0010 percent, 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 a 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 hydrochloric acid by a DCS control reaction kettle system capable of regulating 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 to carry out hydrochloric acid dropwise adding when the pH value is larger 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%, obtaining 1482kg of crude product 2 of atorvastatin mother nucleus M4, detecting by HPLC, wherein the content of atorvastatin mother nucleus M4 in the crude product 2 is 98.87%, the water content is 0.018%, and the content of each impurity is as follows: 0.085% of impurity II (defluorinated impurity), 0.03% of impurity III (m-fluoro impurity), 0.010% of impurity I (o-fluoro impurity), 0.01% of impurity IV (compound III), 0.23% of impurity V (dibromo impurity of compound III), 1.15% of unknown impurity RRT and 0.025%;
(2) Sequentially adding a whole batch of atorvastatin mother nucleus M4 crude products 2 and 4950kg 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 a DCS control reaction kettle system capable of regulating 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 carry out hydrochloric acid dropwise adding when the pH value is greater than the interval value, closing the second electric control valve 42 when the pH value is 5.75, and stopping dropwise adding; the mixed solvent is a mixed solvent of methanol and dichloromethane, wherein the mass fraction of the methanol is 45%;
then, the mixture is heated and refluxed for 1 hour at the temperature of 40 to 50 ℃, and is filtered while the mixture is hot, the filtrate is concentrated and recycled under normal pressure at the temperature of 65 ℃ to obtain 3000kg of mixed solvent, the concentrated solution is cooled to 5 to 10 ℃, the temperature is kept for 1 hour, the mixture is centrifuged, and the mixture is dried for 4 hours at the temperature of 65 ℃ under reduced pressure (the vacuum degree is 0.09 MPa), thus obtaining 1401kg of refined atorvastatin mother nucleus M4;
the weight yield of the refined product is 95.14 percent based on the crude product 2 of the atorvastatin mother nucleus M4, and the content of the atorvastatin mother nucleus M4 is 99.92 percent, the content of the impurity di (defluorinated impurity) is 0.025 percent, the impurity tri (M-fluoro impurity), the impurity mono (o-fluoro impurity), the impurity penta (dibromo impurity of the compound III) and the impurity penta (dibromo impurity of the compound III) are not detected, the unknown impurity RRT is 1.15, the content is 0.002 percent, 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 crude atorvastatin mother nucleus M4 (namely a compound VI) 1 into a reaction kettle with the volume of 5000L, adding 5000kg of water, stirring and mixing, dripping hydrochloric acid to adjust the pH value, controlling the dripping amount of hydrochloric acid by controlling the reaction kettle system through a DCS capable of regulating 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 to drip 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 dripping;
pulping for 2 hours at room temperature, centrifuging, drying under reduced pressure, controlling the water content to be less than or equal to 1%, obtaining 1485kg of crude product 2 of atorvastatin mother nucleus M4, detecting by HPLC, wherein the content of atorvastatin mother nucleus M4 in the crude product 2 is 99.20%, the water content is 0.045%, and the content of each impurity is as follows: 0.080% of impurity II (defluorinated impurity), 0.03% of impurity III (m-fluoro impurity), 0.010% of impurity I (o-fluoro impurity), 0.01% of impurity IV (compound III), 0.21% of impurity V (dibromo impurity of compound III), 1.15% of unknown impurity RRT and 0.021%;
(2) Sequentially adding a whole batch of atorvastatin mother nucleus M4 crude products 2 and 4905kg 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 a DCS control reaction kettle system capable of regulating 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 carry out hydrochloric acid dropwise adding when the pH value is greater than the interval value, closing the second electric control valve 42 when the pH value is 5.80, and stopping dropwise adding; the mixed solvent is a mixed solvent of methanol and dichloromethane, wherein the mass fraction of the methanol is 45%;
then, the mixture is heated and refluxed for 1 hour at the temperature of 40 to 50 ℃, and is filtered while the mixture is hot, the filtrate is concentrated and recycled under normal pressure at the temperature of 65 ℃ to 2970kg of mixed solvent, the concentrated solution is cooled to 4 to 7 ℃, the temperature is kept for 1 hour, the mixture is centrifuged, and the mixture is dried for 4 hours at the temperature of 65 ℃ under reduced pressure (the vacuum degree is 0.09 MPa) to obtain 1415kg of refined atorvastatin mother nucleus M4;
the weight yield of the refined product is 95.32 percent by taking the crude product 2 of the atorvastatin mother nucleus M4 as a reference, and the content of the atorvastatin mother nucleus M4 is 99.95 percent, the content of the impurity di (defluorinated impurity) is 0.020 percent, the impurity tri (M-fluoro impurity), the impurity mono (o-fluoro impurity), the impurity penta (dibromo impurity of the compound III) and the impurity penta (dibromo impurity of the compound III) are not detected, the unknown impurity RRT is 1.15, the content is 0.008 percent, and the melting point is 202.2-203.5 ℃.
Comparative example 1
The refining step in comparative example 1 is basically the same as that in example 2, except that hydrochloric acid is not added to adjust the pH value in step (1), pulping is directly carried out, and the finally obtained crude product 2 of atorvastatin mother nucleus M4 contains unknown impurity RRT1.15 and the content is 0.7% after detection; in the step (2), glacial acetic acid is not added to adjust the pH value, and the temperature reflux is directly carried out, so that the obtained refined atorvastatin mother nucleus M4 contains unknown impurities RRT1.15 and 0.5 percent of impurities through detection.
Comparing comparative example 1 with example 2, it can be seen that the reduction of the content of the unknown impurity RRT1.15 can be achieved by precisely controlling the pH value during the reaction, thereby improving the purity and quality of the refined product of atorvastatin mother M4.
The above examples are illustrative of embodiments of the present invention, and embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principles of the present invention should be made by the equivalent substitution manner, and are included in the scope of the present invention.
Claims (8)
1. The refining method of the atorvastatin mother nucleus M4 is characterized by comprising the following steps of:
(1) Mixing the crude product 1 of the atorvastatin mother nucleus M4 with water, stirring for dissolving, and adding acid to adjust the pH value to 5.60-6.40; pulping for 2-3 hours at room temperature, centrifuging, and drying to obtain crude atorvastatin mother nucleus M4 2;
(2) Mixing the crude product 2 of the atorvastatin mother core M4 in the step (1) with a mixed solvent, stirring for dissolution, and adding acid to adjust the pH value to 5.7-5.8; then carrying out heat reflux for 1-3 hours at the temperature of 35-50 ℃, carrying out suction filtration while the filtrate is hot, concentrating the filtrate at normal pressure at the temperature of 60-65 ℃, 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 a refined product of the atorvastatin mother nucleus M4;
the mass ratio of the crude product 1 of the atorvastatin mother M4 to water in the step (1) is 1:3.0 to 5.0;
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%;
in the step (2), the mass ratio of the crude product 2 of the atorvastatin mother core M4 to the mixed solvent is 1: 3-3.5.
2. The refining method according to claim 1, wherein in the step (1), the pH value is adjusted by using an inorganic acid selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.
3. The refining method as claimed in claim 1, wherein the pH value in the step (1) is adjusted to 5.95 to 6.15 by hydrochloric acid.
4. The refining method according to claim 1, wherein the drying in the step (1) is performed until the water content is not more than 1%.
5. The refining method according to claim 1, wherein the mass fraction of methanol in the mixed solvent in the step (2) is 45%.
6. The refining method 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 refining method according to claim 1, wherein in the step (2), glacial acetic acid is used to adjust the pH to 5.75.
8. The purification method according to claim 1, wherein the amount of the mixed solvent recovered by normal pressure concentration in the step (2) is 55 to 65% of the amount of the original solvent.
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Citations (14)
| 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 |
| CN101805279A (en) * | 2010-01-22 | 2010-08-18 | 绍兴民生医药有限公司 | Preparation method of atorvastatin calcium |
| 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 |
| 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 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006021968A1 (en) * | 2004-08-26 | 2006-03-02 | Biocon Limited | PROCESS FOR PREPARATION OF 4-FLUORO-α-[2-METHYL-1-OXOPROPYL]Ϝ-OXO-N-β-DIPHENYLBENZENE BUTANE AMIDE |
| EP1922301A1 (en) * | 2005-09-09 | 2008-05-21 | Pfizer Science and Technology Ireland Limited | Preparation of an atorvastatin intermediate |
| US20080280970A1 (en) * | 2007-05-08 | 2008-11-13 | Czarnik Anthony W | Deuterium-enriched atorvastatin |
| WO2009019561A2 (en) * | 2007-08-03 | 2009-02-12 | Pfizer Products Inc. | Process for preparing chiral compounds |
| WO2009144736A1 (en) * | 2008-05-29 | 2009-12-03 | Arch Pharmalabs Limited | NOVEL PROCESS FOR THE PREPARATION OF 4-FLUORO-ALPHA-[2-METHYL -1-OXOPROPYL]-GAMMA-OXO-N-ß-DIPHENYLBENZENEBUTANAMIDE AND PRODUCTS THEREFROM |
| GB2479830A (en) * | 2010-04-23 | 2011-10-26 | Helvetica Ind | Phosphine oxide and phosphonate pyrrole derivatives |
| WO2012143933A1 (en) * | 2011-04-21 | 2012-10-26 | Vijayasri Organics Limited | A PROCESS FOR PREPARATION OF 4-FLUORO-α-[2-METHYL-L-OXOPROPYL]-γ-OXO-N-β-DIPHENYLBENZENE BUTANE AMIDE |
-
2021
- 2021-12-31 CN CN202111659985.5A patent/CN114195670B/en active Active
Patent Citations (14)
| 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 |
| CN101805279A (en) * | 2010-01-22 | 2010-08-18 | 绍兴民生医药有限公司 | Preparation method of atorvastatin calcium |
| 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 (6)
| Title |
|---|
| An Efficient Synthesis of Highly Substituted Pyrrole and Bis Pyrrole Derivatives;Rajeshwar Reddy Sagyam et al.;《J. Heterocyclic Chem.》;第44卷;第923-926页 * |
| 傅超美 等.《中药药剂学》.中国医药科技出版社,2018,(第2018年8月第2版),第84页. * |
| 罗永明.《中药化学成分提取分离技术与方法》.上海科学技术出版社,2016,(第2016年1月第1版),第133-134页. * |
| 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》.2005,第15卷(第1期),第48-50页. * |
| 阿托伐他汀钙中间体的合成工艺研究;饶历 等;《武汉工程大学学报》;第32卷(第12期);第10-12页 * |
| 阿托伐他汀钙母核的合成及工艺研究;邢玉芝 等;《中国优秀硕士学位论文全文数据库 工程科技I辑》;第1-68页 * |
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