CN113549039A - Preparation method of mycophenolate mofetil impurity A - Google Patents
Preparation method of mycophenolate mofetil impurity A Download PDFInfo
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- CN113549039A CN113549039A CN202010327998.1A CN202010327998A CN113549039A CN 113549039 A CN113549039 A CN 113549039A CN 202010327998 A CN202010327998 A CN 202010327998A CN 113549039 A CN113549039 A CN 113549039A
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- QGQXAMBOYWULFX-LZWSPWQCSA-N 2-morpholin-4-ylethyl (e)-6-(4,6-dihydroxy-7-methyl-3-oxo-1h-2-benzofuran-5-yl)-4-methylhex-4-enoate Chemical compound OC=1C=2C(=O)OCC=2C(C)=C(O)C=1C\C=C(/C)CCC(=O)OCCN1CCOCC1 QGQXAMBOYWULFX-LZWSPWQCSA-N 0.000 title claims abstract description 58
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 72
- 238000003756 stirring Methods 0.000 claims description 61
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 46
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 claims description 39
- 229960004866 mycophenolate mofetil Drugs 0.000 claims description 38
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 36
- 238000001816 cooling Methods 0.000 claims description 26
- 239000000243 solution Substances 0.000 claims description 26
- 239000012043 crude product Substances 0.000 claims description 25
- 238000010992 reflux Methods 0.000 claims description 25
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 23
- 238000001914 filtration Methods 0.000 claims description 22
- 239000000706 filtrate Substances 0.000 claims description 15
- 239000011259 mixed solution Substances 0.000 claims description 15
- 238000010438 heat treatment Methods 0.000 claims description 14
- 238000005406 washing Methods 0.000 claims description 14
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 13
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 13
- BLQJIBCZHWBKSL-UHFFFAOYSA-L magnesium iodide Chemical compound [Mg+2].[I-].[I-] BLQJIBCZHWBKSL-UHFFFAOYSA-L 0.000 claims description 13
- 229910001641 magnesium iodide Inorganic materials 0.000 claims description 13
- 238000004321 preservation Methods 0.000 claims description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- 239000005457 ice water Substances 0.000 claims description 12
- 239000011541 reaction mixture Substances 0.000 claims description 12
- 239000012535 impurity Substances 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000012074 organic phase Substances 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 5
- 239000006227 byproduct Substances 0.000 abstract description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 40
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 22
- 229910052757 nitrogen Inorganic materials 0.000 description 20
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 235000017557 sodium bicarbonate Nutrition 0.000 description 11
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
- 239000012065 filter cake Substances 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- 238000004537 pulping Methods 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- 238000012790 confirmation Methods 0.000 description 9
- 239000003814 drug Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000002054 transplantation Methods 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 3
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical class OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 229960000951 mycophenolic acid Drugs 0.000 description 2
- DZCBKUAAGVVLOX-UHFFFAOYSA-N 1-morpholin-4-ylethanol Chemical compound CC(O)N1CCOCC1 DZCBKUAAGVVLOX-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- KKFDCBRMNNSAAW-UHFFFAOYSA-N 2-(morpholin-4-yl)ethanol Chemical compound OCCN1CCOCC1 KKFDCBRMNNSAAW-UHFFFAOYSA-N 0.000 description 1
- -1 2-ethylmorpholine ester derivative of mycophenolic acid (MPA) Chemical class 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 208000032759 Hemolytic-Uremic Syndrome Diseases 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 229940107810 cellcept Drugs 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical class O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000009256 replacement therapy Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of high-purity mycophenolate mofetil impurity A, and compared with the prior art, the method provided by the invention has the advantages of high reaction yield, good reaction selectivity, less by-products and high purity of target products.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a preparation method and application of mycophenolate mofetil impurity A.
Background
Mycophenolate mofetil (E-6- (1, 3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl) -4-methyl-4-hexenoic acid-2-morpholinoethyl ester) has a structure shown in formula I, and is a 2-ethylmorpholine ester derivative of mycophenolic acid (MPA) shown in formula II.
Mycophenolate mofetil, also known as Mycophenolate Mofetil (MMF), has the trade name Cellcept, was developed by Syntex corporation of America and is a semi-synthetic derivative of mycophenolic acid (MPA) isolated from Penicillinlinglauum zymolyte of mould. Mycophenolate mofetil is a replication competent cell inhibitor, has been clinically used for many years, and is mainly used for treating psoriasis. By the end of the 20 th century and the 80 s, organ transplantation animal experiments prove that the survival time of rodent and dog allograft kidney, heart, pancreatic islet and the like can be remarkably prolonged. Sollinger and the like successfully apply MMF to the treatment of the rejection reaction of the kidney transplantation for the first time, and the treatment effect is obvious. The mycophenolate mofetil can specifically inhibit the activity of hypoxanthine nucleotide dehydroacid (1MPDH) in a lymphocyte purine de novo synthesis pathway, so that the mycophenolate mofetil has a strong function of inhibiting lymphocyte proliferation; mycophenolate mofetil has the functions of maintaining immunosuppression treatment for patients after kidney and heart transplantation and is used as a replacement therapy for patients after transplantation, which have serious nephrotoxicity, hemolytic uremic syndrome and other toxicities caused by cyclosporin treatment.
Mycophenolate mofetil is disclosed for the first time in patent US4753935, and several different synthetic methods have been reported later, for example, patent CA2493508 reports a method using zinc powder, zinc salt and zinc oxide as catalysts, patent WO00/34503 reports an enzymatic method; the process route not only increases the production cost due to the addition of the catalyst, but also increases the steps of adding and separating the catalyst; patent US4753935 reports a process for the production of mycophenolate mofetil by reacting mycophenolic acid with an acid chloride to produce an acid chloride intermediate, which is then reacted with morpholinoethanol; the patent US5247083 provides a technical scheme as follows: in a proper solvent or solvent mixture, mycophenolic acid and 2-morpholinoethanol are refluxed, azeotroped and dehydrated to prepare mycophenolate mofetil, longer reaction time is needed for achieving sufficient conversion rate, and the defects of darker product color and low product yield exist.
Although the prior literature discloses various methods for synthesizing mycophenolate mofetil, the prior literature inevitably generates impurities which remain in the raw material medicine. It is known that impurities in a pharmaceutically active ingredient are inevitably required in various processes of production of a raw material drug or production of a formulation for comprehensive research and analytical tests such as content, pharmacological and toxicological activity, and the like. In the EP drug standard of mycophenolate mofetil, 8 specific impurities such as impurity A-impurity H and the like are listed in detail, wherein the structural formula of the specific impurity A is shown as follows. Although the prior literature also reports related impurity detection and analysis methods and provides a certain basis for researching the content of impurities in active ingredients, the prior literature does not report a high-efficiency and feasible preparation method of related impurities, particularly the impurity A. In order to provide a complete related substance reference substance for the quality research of a mycophenolate mofetil raw material medicament or a medicinal preparation containing mycophenolate mofetil, improve the quality standard of mycophenolate mofetil and provide important guidance for safe medication, a preparation method of a high-purity mycophenolate mofetil impurity A needs to be provided, and the structure of the mycophenolate mofetil impurity A is as follows:
disclosure of Invention
The invention aims to provide a technical method for preparing mycophenolate mofetil impurity A, which has the advantages of simple operation, mild reaction conditions, high product yield and high purity and is suitable for large-scale production. The purity of the mycophenolate mofetil impurity A prepared by the method is up to more than 99%, and the mycophenolate mofetil impurity A can be directly used for the quality research of mycophenolate mofetil.
The specific technical content of the invention is as follows:
the invention provides a preparation method of mycophenolate mofetil impurity A, which comprises the following steps:
step a: mixing and dissolving mycophenolate mofetil and magnesium iodide in an organic solvent, cooling, dropwise adding a boron tribromide solution under stirring, heating after dropwise adding is finished, and carrying out heat preservation reaction; after the reaction is finished, adding the reaction mixture into a proper amount of ice-water mixture, separating liquid and retaining an organic phase, washing, drying by anhydrous sodium sulfate, and evaporating to dryness under reduced pressure to obtain a crude product of mycophenolate mofetil impurity A;
step b: heating, refluxing and dissolving the mycophenolate mofetil impurity A crude product in an organic solvent, adding activated carbon to continue refluxing after dissolution, carrying out heat filtration, and cooling and crystallizing filtrate to obtain high-purity mycophenolate mofetil impurity A.
Preferably, the organic solvent in step a is dichloromethane, chloroform or carbon tetrachloride.
Preferably, the mass-to-volume ratio of the mycophenolate mofetil to the organic solvent in the step a is 1: 10-15 g/ml.
Preferably, the temperature of the temperature reduction in the step a is-15 to-10 ℃.
Preferably, the solution of boron tribromide in the step a is a dichloromethane solution of boron tribromide, and further preferably, the mass-to-volume ratio of the two is 1: 2-4, g/ml.
Preferably, the temperature rise in the step a is 25-50 ℃, and preferably 30-35 ℃.
Preferably, the time of the heat preservation reaction in the step a is 2-8 hours, and preferably 3-4 hours.
Preferably, the molar ratio of mycophenolate mofetil to boron tribromide in the step a is 1: 3-5, and preferably 1: 4.
Preferably, the molar ratio of mycophenolate mofetil to magnesium iodide in step a is 1: 0.1-0.3, preferably 1: 0.2.
Preferably, the washing process described in step a is a separate washing using a 5% aqueous solution of sodium bicarbonate and a saturated saline solution.
Preferably, the organic solvent in step b is a mixed solution of butyl acetate and ethanol; the volume ratio of the butyl acetate to the ethanol in the mixed solution is 1: 2-4, and preferably 1: 3.
Preferably, the mass-to-volume ratio (g/ml) of the mycophenolate mofetil crude product to the mixed solution in the step b is 1: 8-12, and preferably 1: 10.
Preferably, the refluxing time in the step b is 0.5-2 h, and preferably 0.5 h.
Preferably, the cooling crystallization process in step b is as follows: in the first stage, the temperature of the filtrate is reduced to 35-40 ℃, and the filtrate is stirred for 2-3 hours; and the second stage is continuously cooled to-10-0 ℃, and stirred for crystallization for 3-4 hours.
Compared with the prior art, the invention has the following technical effects:
the invention provides a preparation method of high-purity mycophenolate mofetil impurity A, which has the advantages of high reaction yield, good reaction selectivity, less by-products and high purity of target products.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.
Example 1
Under the protection of nitrogen, 43.35g of mycophenolate mofetil and 5.56g of magnesium iodide are added into a three-necked bottle, 433.5ml of dichloromethane is added, the temperature is reduced to-15 to-10 ℃ by stirring, 200ml of dichloromethane solution containing 100.20g of boron tribromide is added dropwise under stirring (the mass ratio is 1: 2), after the dropwise addition is finished, the temperature is slowly increased to 30 to 35 ℃, and the reaction is carried out for 3 to 4 hours under heat preservation. After completion of the reaction, the reaction mixture was added to 1500ml of an ice-water mixture with stirring, the mixture was separated, and the organic layer was washed with 200ml of 5% aqueous sodium bicarbonate solution, 200ml of saturated brine, dried over anhydrous sodium sulfate for 4 hours, and evaporated to dryness under reduced pressure to obtain 37.8g of a crude mycophenolate mofetil impurity A.
Adding 37.8g of mycophenolate mofetil impurity A crude product into a three-necked bottle under the protection of nitrogen, adding 380ml of mixed solution (volume ratio is 1: 3) of butyl acetate and ethanol, stirring and heating to reflux, adding 3.4g of activated carbon after the mycophenolate mofetil impurity A crude product is dissolved, continuously refluxing for 30 minutes, carrying out hot filtration, cooling the filtrate to 35-40 ℃, stirring and crystallizing for 2-3 hours, cooling to-10-0 ℃, stirring and crystallizing for 3-4 hours, filtering, pulping and washing a filter cake by using 30ml of ethanol, and drying under reduced pressure to obtain 34.5g of mycophenolate mofetil impurity A, and carrying out HPLC: 99.32% (using the HPLC detection method described in the mycophenolate mofetil EP quality Standard). MS (M/z) 421.1046[ M +2H]+；1HNMR(400MHz,DMSO-d6)δ12.05(s,1H),8.76 (s,1H),6.01～5.98(t,J＝16.0Hz,1H),5.45(s,2H),4.47～4.40(m,2H),3.63～3.56(m,4H),3.29～3.27(d,J＝8. 0Hz,2H),3.10～3.06(t,J＝16.0Hz,2H),2.59～2.53(m,4H),2.44～2.37(m,4H),2.15(s,3H),1.87(s,3H).13 CNMR(100MHz,DMSO-d6)δ175.5,168.2,163.6,158.8,150.3,138.3,124.0,113.5,112.7,111.4,68.5, 67.6(2C),63.2,57.2(2C),55.6,36.6,34.4,24.3,15.4,12.2.
Example 2
Under the protection of nitrogen, 43.35g of mycophenolate mofetil and 2.78g of magnesium iodide are added into a three-necked bottle, 520ml of dichloromethane is added, the temperature is reduced to-15 to-10 ℃ by stirring, 150ml of dichloromethane solution containing 75.15g of boron tribromide is dropwise added under stirring (the mass ratio is 1: 2), after the dropwise addition is finished, the temperature is slowly increased to 30-35 ℃, and the heat preservation reaction is carried out for 3-4 hours. After completion of the reaction, the reaction mixture was added to 1500ml of an ice-water mixture with stirring, the mixture was separated, and the organic layer was washed with 200ml of 5% aqueous sodium bicarbonate solution, 200ml of saturated brine, dried over anhydrous sodium sulfate for 4 hours, and evaporated to dryness under reduced pressure to obtain 35.7g of a crude mycophenolate mofetil impurity A.
Adding 35.7g of mycophenolate mofetil impurity A crude product into a three-necked bottle under the protection of nitrogen, adding 360ml of mixed solution (volume ratio is 1: 3) of butyl acetate and ethanol, stirring and heating to reflux, adding 3.4g of activated carbon after the mycophenolate mofetil impurity A crude product is dissolved, continuously refluxing for 30 minutes, carrying out hot filtration, cooling the filtrate to 35-40 ℃, stirring and crystallizing for 2-3 hours, cooling to-10-0 ℃, stirring and crystallizing for 3-4 hours, filtering, pulping and washing a filter cake by using 30ml of ethanol, and drying under reduced pressure to obtain 32.4g of mycophenolate mofetil impurity A, and carrying out HPLC: 99.31%, the structure confirmation data are the same as in example 1.
Example 3
Under the protection of nitrogen, 43.35g of mycophenolate mofetil and 8.34g of magnesium iodide are added into a three-necked bottle, 650ml of dichloromethane is added, the temperature is reduced to-15 to-10 ℃ by stirring, 250ml of dichloromethane solution containing 125.26g of boron tribromide is dropwise added under stirring (the mass ratio is 1: 2), after the dropwise addition is finished, the temperature is slowly increased to 30-35 ℃, and the heat preservation reaction is carried out for 3-4 hours. After completion of the reaction, the reaction mixture was added to 1500ml of an ice-water mixture with stirring, the mixture was separated, and the organic layer was washed with 200ml of 5% aqueous sodium bicarbonate solution, 200ml of saturated brine, dried over anhydrous sodium sulfate for 4 hours, and evaporated to dryness under reduced pressure to obtain 35.9g of a crude mycophenolate mofetil impurity A.
Adding 35.9g of mycophenolate mofetil impurity A crude product into a three-necked bottle under the protection of nitrogen, adding 360ml of mixed solution (volume ratio is 1: 3) of butyl acetate and ethanol, stirring and heating to reflux, adding 3.4g of activated carbon after the mycophenolate mofetil impurity A crude product is dissolved, continuously refluxing for 30 minutes, carrying out hot filtration, cooling the filtrate to 35-40 ℃, stirring and crystallizing for 2-3 hours, cooling to-10-0 ℃, stirring and crystallizing for 3-4 hours, filtering, pulping and washing a filter cake with 30ml of ethanol, and drying under reduced pressure to obtain 32.6g of mycophenolate mofetil impurity A, and carrying out HPLC: 99.31%, the structure confirmation data are the same as in example 1.
Example 4
Under the protection of nitrogen, 43.35g of mycophenolate mofetil and 5.56g of magnesium iodide are added into a three-necked bottle, 433ml of dichloromethane is added, the temperature is reduced to-15 to-10 ℃ by stirring, 200ml of dichloromethane solution containing 100g of boron tribromide is dropwise added under stirring (the mass ratio is 1: 2), after the dropwise addition is finished, the temperature is slowly increased to 30-35 ℃, and the heat preservation reaction is carried out for 3-4 hours. After completion of the reaction, the reaction mixture was added to 1500ml of an ice-water mixture with stirring, the mixture was separated, and the organic layer was washed with 200ml of 5% aqueous sodium bicarbonate solution, 200ml of saturated brine, dried over anhydrous sodium sulfate for 4 hours, and evaporated to dryness under reduced pressure to obtain 37.9g of a crude mycophenolate mofetil impurity A.
Adding 37.9g of mycophenolate mofetil impurity A crude product into a three-necked bottle under the protection of nitrogen, adding 300ml of mixed solution (volume ratio is 1: 2) of butyl acetate and ethanol, stirring and heating to reflux, adding 3.4g of activated carbon after the mycophenolate mofetil impurity A crude product is dissolved, continuously refluxing for 30 minutes, carrying out hot filtration, cooling the filtrate to 35-40 ℃, stirring and crystallizing for 2-3 hours, cooling to-10-0 ℃, stirring and crystallizing for 3-4 hours, filtering, pulping and washing a filter cake by using 30ml of ethanol, and drying under reduced pressure to obtain 31.7g of mycophenolate mofetil impurity A, and carrying out HPLC: 98.82%, the data for structure confirmation are the same as in example 1.
Example 5
Under the protection of nitrogen, 43.35g of mycophenolate mofetil and 5.56g of magnesium iodide are added into a three-necked bottle, 433.5ml of dichloromethane is added, the temperature is reduced to-15 to-10 ℃ by stirring, 150ml of dichloromethane solution containing 100.20g of boron tribromide is added dropwise under stirring (the mass ratio is 1: 2), after the dropwise addition is finished, the temperature is slowly increased to 30 to 35 ℃, and the reaction is carried out for 3 to 4 hours under heat preservation. After completion of the reaction, the reaction mixture was added to 1500ml of an ice-water mixture with stirring, the mixture was separated, and the organic layer was washed with 200ml of 5% aqueous sodium bicarbonate solution, 200ml of saturated brine, dried over anhydrous sodium sulfate for 4 hours, and evaporated to dryness under reduced pressure to obtain 37.6g of a crude mycophenolate mofetil impurity A.
Adding 37.6g of mycophenolate mofetil impurity A crude product into a three-necked bottle under the protection of nitrogen, adding 450ml of mixed solution (volume ratio is 1: 4) of butyl acetate and ethanol, stirring and heating to reflux, adding 3.4g of activated carbon after the mycophenolate mofetil impurity A crude product is dissolved, continuously refluxing for 30 minutes, carrying out hot filtration, cooling the filtrate to 35-40 ℃, stirring and crystallizing for 2-3 hours, cooling to-10-0 ℃, stirring and crystallizing for 3-4 hours, filtering, pulping and washing a filter cake by using 30ml of ethanol, and drying under reduced pressure to obtain 32.2g of mycophenolate mofetil impurity A, and carrying out HPLC: 98.79%, the structure confirmation data are the same as in example 1.
Example 6
Under the protection of nitrogen, 43.35g of mycophenolate mofetil and 11.12g of magnesium iodide are added into a three-necked bottle, 430ml of dichloromethane is added, the temperature is reduced to-15 to-10 ℃ by stirring, 200ml of dichloromethane solution containing 100g of boron tribromide is dropwise added under stirring (the mass ratio is 1: 2), after the dropwise addition is finished, the temperature is slowly increased to 30-35 ℃, and the heat preservation reaction is carried out for 3-4 hours. After completion of the reaction, the reaction mixture was added to 1500ml of an ice-water mixture with stirring, the mixture was separated, and the organic layer was washed with 200ml of 5% aqueous sodium bicarbonate solution, 200ml of saturated brine, dried over anhydrous sodium sulfate for 4 hours, and evaporated to dryness under reduced pressure to give 33.7g of a crude mycophenolate mofetil impurity A.
Adding 33.7g of mycophenolate mofetil impurity A crude product into a three-necked bottle under the protection of nitrogen, adding 340ml of mixed solution (volume ratio is 1: 3) of butyl acetate and ethanol, stirring and heating to reflux, adding 3.4g of activated carbon after the mycophenolate mofetil impurity A crude product is dissolved, continuously refluxing for 30 minutes, carrying out hot filtration, cooling the filtrate to 35-40 ℃, stirring and crystallizing for 2-3 hours, cooling to-10-0 ℃, stirring and crystallizing for 3-4 hours, filtering, pulping and washing a filter cake by using 30ml of ethanol, and drying under reduced pressure to obtain 30.3g of mycophenolate mofetil impurity A, and carrying out HPLC: 99.29%, the data for structure confirmation are the same as in example 1.
Example 7
Under the protection of nitrogen, 43.35g of mycophenolate mofetil and 1.39g of magnesium iodide are added into a three-necked bottle, 433.5ml of dichloromethane is added, the temperature is reduced to-15 to-10 ℃ by stirring, 150ml of dichloromethane solution containing 100.20g of boron tribromide is added dropwise under stirring (the mass ratio is 1: 2), after the dropwise addition is finished, the temperature is slowly increased to 30 to 35 ℃, and the reaction is carried out for 3 to 4 hours under heat preservation. After completion of the reaction, the reaction mixture was added to 1500ml of an ice-water mixture with stirring, the mixture was separated, and the organic layer was washed with 200ml of 5% aqueous sodium bicarbonate solution, 200ml of saturated brine, dried over anhydrous sodium sulfate for 4 hours, and evaporated to dryness under reduced pressure to obtain 29.5g of a crude mycophenolate mofetil impurity A.
Under the protection of nitrogen, adding 29.5g of mycophenolate mofetil impurity A crude product into a three-necked bottle, adding 320ml of mixed solution (volume ratio is 1: 3) of butyl acetate and ethanol, stirring and heating to reflux, adding 3.4g of activated carbon after the mycophenolate mofetil impurity A crude product is dissolved, continuously refluxing for 30 minutes, carrying out hot filtration, cooling the filtrate to 35-40 ℃, stirring and crystallizing for 2-3 hours, cooling to-10-0 ℃, stirring and crystallizing for 3-4 hours, filtering, pulping and washing a filter cake with 30ml of ethanol, and drying under reduced pressure to obtain 24.8g of mycophenolate mofetil impurity A, and carrying out HPLC: 99.32%, the structure confirmation data are the same as in example 1.
Example 8
Under the protection of nitrogen, 43.35g of mycophenolate mofetil and 5.56g of magnesium iodide are added into a three-necked bottle, 433.5ml of dichloromethane is added, the temperature is reduced to-5-0 ℃ under stirring, 300ml of dichloromethane solution containing 150.10g of boron tribromide is dropwise added under stirring (the mass ratio is 1: 2), after the dropwise addition is finished, the temperature is slowly increased to 30-35 ℃, and the heat preservation reaction is carried out for 3-4 hours. After completion of the reaction, the reaction mixture was added to 1500ml of an ice-water mixture with stirring, the mixture was separated, and the organic layer was washed with 200ml of 5% aqueous sodium bicarbonate solution, 200ml of saturated brine, dried over anhydrous sodium sulfate for 4 hours, and evaporated to dryness under reduced pressure to obtain 30.5g of a crude mycophenolate mofetil impurity A.
Under the protection of nitrogen, adding 30.5g of mycophenolate mofetil impurity A crude product into a three-necked bottle, adding 330ml of mixed solution (volume ratio is 1: 5) of butyl acetate and ethanol, stirring and heating to reflux, adding 3.4g of activated carbon after the mycophenolate mofetil impurity A crude product is dissolved, continuously refluxing for 30 minutes, carrying out hot filtration, cooling the filtrate to 35-40 ℃, stirring and crystallizing for 2-3 hours, cooling to-10-0 ℃, stirring and crystallizing for 3-4 hours, filtering, pulping and washing a filter cake with 30ml of ethanol, and drying under reduced pressure to obtain 24.5g of mycophenolate mofetil impurity A, and carrying out HPLC: 98.30%, the structure confirmation data are the same as in example 1.
Example 9
Under the protection of nitrogen, 43.35g of mycophenolate mofetil and 8.34g of magnesium iodide are added into a three-necked bottle, 650ml of dichloromethane is added, the temperature is reduced to-15 to-10 ℃ by stirring, 250ml of dichloromethane solution containing 125.26g of boron tribromide is dropwise added under stirring (the mass ratio is 1: 2), after the dropwise addition is finished, the temperature is slowly increased to 30-35 ℃, and the heat preservation reaction is carried out for 3-4 hours. After completion of the reaction, the reaction mixture was added to 1500ml of an ice-water mixture with stirring, the mixture was separated, and the organic layer was washed with 200ml of 5% aqueous sodium bicarbonate solution, 200ml of saturated brine, dried over anhydrous sodium sulfate for 4 hours, and evaporated to dryness under reduced pressure to obtain 35.7g of a crude mycophenolate mofetil impurity A.
Adding 35.7g of mycophenolate mofetil impurity A crude product into a three-necked bottle under the protection of nitrogen, adding 360ml of mixed solution (volume ratio is 1: 3) of butyl acetate and ethanol, stirring and heating to reflux, adding 3.4g of activated carbon after the mycophenolate mofetil impurity A crude product is dissolved, continuously refluxing for 30 minutes, carrying out hot filtration, cooling to-10-0 ℃, stirring and crystallizing for 3-4 hours, filtering, pulping and washing a filter cake with 30ml of ethanol, and drying under reduced pressure to obtain 24.6g of mycophenolate mofetil impurity A, and carrying out HPLC: 98.17%, the structure confirmation data are the same as in example 1.
Comparative example 1
Under the protection of nitrogen, 43.35g of mycophenolate mofetil is added into a three-necked bottle, 430ml of dichloromethane is added, the temperature is reduced to-15 to-10 ℃ under stirring, 200ml of dichloromethane solution containing 100.20g of boron tribromide is dropwise added under stirring (the mass ratio is 1: 2), after the dropwise addition is finished, the temperature is slowly increased to 30-35 ℃, and the heat preservation reaction is carried out for 3-4 hours. After completion of the reaction, the reaction mixture was added to 1500ml of an ice-water mixture with stirring, the mixture was separated, and the organic layer was washed with 200ml of 5% aqueous sodium bicarbonate solution, 200ml of saturated brine, dried over anhydrous sodium sulfate for 4 hours, and evaporated to dryness under reduced pressure to obtain 21.5g of a crude mycophenolate mofetil impurity a.
Under the protection of nitrogen, adding 21.5g of mycophenolate mofetil impurity A crude product into a three-necked bottle, adding 220ml of mixed solution (volume ratio is 1: 3) of butyl acetate and ethanol, stirring and heating to reflux, adding 3.4g of activated carbon after the mycophenolate mofetil impurity A crude product is dissolved, continuously refluxing for 30 minutes, carrying out hot filtration, cooling the filtrate to 35-40 ℃, stirring and crystallizing for 2-3 hours, cooling to-10-0 ℃, stirring and crystallizing for 3-4 hours, filtering, pulping and washing a filter cake with 30ml of ethanol, and drying under reduced pressure to obtain 18.0g of mycophenolate mofetil impurity A, and carrying out HPLC: 98.13%, the structure confirmation data are the same as in example 1.
Claims (10)
1. A preparation method of mycophenolate mofetil impurity A is characterized in that the impurity A is as follows:
the preparation method comprises the following steps:
step a: mixing and dissolving mycophenolate mofetil and magnesium iodide in an organic solvent, cooling, dropwise adding a boron tribromide solution under stirring, heating after dropwise adding is finished, and carrying out heat preservation reaction; after the reaction is finished, adding the reaction mixture into a proper amount of ice-water mixture, separating liquid and retaining an organic phase, washing, drying by anhydrous sodium sulfate, and evaporating to dryness under reduced pressure to obtain a crude product of mycophenolate mofetil impurity A;
step b: heating, refluxing and dissolving the mycophenolate mofetil impurity A crude product in an organic solvent, adding activated carbon to continue refluxing after dissolution, carrying out heat filtration, and cooling and crystallizing filtrate to obtain high-purity mycophenolate mofetil impurity A.
2. The method of claim 1, wherein the organic solvent in step a is dichloromethane, chloroform or carbon tetrachloride.
3. The method of claim 1, wherein the temperature of the cooling in step a is-15 to-10 ℃.
4. The preparation method according to claim 1, wherein the solution of boron tribromide in the step a is a dichloromethane solution of boron tribromide, and the mass-to-volume ratio of the two is 1: 2-4, g/ml.
5. The method according to claim 1, wherein the temperature of the elevated temperature in the step a is 25 to 50 ℃.
6. The method of claim 1, wherein the molar ratio of mycophenolate mofetil to boron tribromide in step a is 1:3 to 5.
7. The method of claim 1, wherein the molar ratio of mycophenolate mofetil to magnesium iodide in step a is 1:0.1 to 0.3.
8. The method according to claim 1, wherein the organic solvent in step b is a mixed solution of butyl acetate and ethanol.
9. The preparation method of claim 1, wherein the mass-to-volume ratio of the crude mycophenolate mofetil to the mixed solution in step b is 1: 8-12 g/ml.
10. The preparation method according to claim 1, wherein the cooling crystallization process in the step b is as follows: in the first stage, the temperature of the filtrate is reduced to 35-40 ℃, and the filtrate is stirred for 2-3 hours; and the second stage is continuously cooled to-10-0 ℃, and stirred for crystallization for 3-4 hours.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106179138A (en) * | 2016-06-28 | 2016-12-07 | 伊科纳诺（北京）科技发展有限公司 | A kind of surface modifying method of aerosil demethylation |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106179138A (en) * | 2016-06-28 | 2016-12-07 | 伊科纳诺（北京）科技发展有限公司 | A kind of surface modifying method of aerosil demethylation |
Non-Patent Citations (2)
| Title |
|---|
| YU -TING LU 等: "Separation and identification of process-related substances and degradation products in mycophenolate mofetil by liquid chromatography coupled with quadrupole-time of flight mass spectrometry", JOURNAL OF SEPARATION SCIENCE * |
| 武利强;杨春广;: "银杏酚的简易合成", 沈阳药科大学学报, no. 06 * |
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