CN117624238A - Zoledronic acid impurity and preparation method thereof - Google Patents
Zoledronic acid impurity and preparation method thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 239000012535 impurity Substances 0.000 title abstract description 19
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 title abstract description 17
- 229960004276 zoledronic acid Drugs 0.000 title abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical class CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 5
- 230000007062 hydrolysis Effects 0.000 claims abstract description 4
- 238000006366 phosphorylation reaction Methods 0.000 claims abstract description 4
- 238000006467 substitution reaction Methods 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 16
- 238000001914 filtration Methods 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 14
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 13
- 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 claims description 10
- 239000007858 starting material Substances 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 239000011230 binding agent Substances 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- 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 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 3
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 3
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 238000004042 decolorization Methods 0.000 claims description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 13
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 abstract description 13
- 238000011160 research Methods 0.000 abstract description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 3
- 231100000027 toxicology Toxicity 0.000 abstract description 3
- 150000002460 imidazoles Chemical class 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- 239000013558 reference substance Substances 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 230000026731 phosphorylation Effects 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 22
- -1 1, 3-bis (2-ethoxy-2-oxoethyl) -2-methyl-1H-imidazol-3-ium Chemical compound 0.000 description 16
- 239000012065 filter cake Substances 0.000 description 14
- 239000000203 mixture Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000000843 powder Substances 0.000 description 8
- 239000012141 concentrate Substances 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 210000000988 bone and bone Anatomy 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N 4-methylimidazole Chemical compound CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 description 4
- 229940122361 Bisphosphonate Drugs 0.000 description 4
- 150000004663 bisphosphonates Chemical class 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 208000001132 Osteoporosis Diseases 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- OBQCWYWUAMLDAT-UHFFFAOYSA-N acetic acid;2-ethyl-5-methyl-1h-imidazole Chemical compound CC(O)=O.CCC1=NC(C)=CN1 OBQCWYWUAMLDAT-UHFFFAOYSA-N 0.000 description 3
- IGIXWAFTABBSIO-UHFFFAOYSA-N acetic acid;5-ethyl-2-methyl-1h-imidazole Chemical compound CC(O)=O.CCC1=CN=C(C)N1 IGIXWAFTABBSIO-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 210000002997 osteoclast Anatomy 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid 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-SXOMAYOGSA-N 0.000 description 1
- 208000010392 Bone Fractures Diseases 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Etidronic acid Chemical compound OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 description 1
- 206010017076 Fracture Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000003076 Osteolysis Diseases 0.000 description 1
- 206010058907 Spinal deformity Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229940124605 anti-osteoporosis drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000037182 bone density Effects 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940009626 etidronate Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 238000013332 literature search Methods 0.000 description 1
- 208000029791 lytic metastatic bone lesion Diseases 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 206010041569 spinal fracture Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to a new impurity of zoledronic acid, which has the following structural characteristics:R 1 selected from H or-CH 3 ；R 2 Selected from H or-CH 3 And R is 1 、R 2 Not simultaneously H; r is R 3 Selected from-CH 2 COO ‑ or-CH 2 C(OH)(PO 3 H 2 ) 2 . The invention also discloses a preparation method of the compound, which is prepared by fully carrying out substitution reaction on methyl substituted imidazole and ethyl bromoacetate, and then carrying out hydrolysis and phosphorylation. The synthesis method disclosed by the invention is simple, the conditions are easy to control, the production safety is high, the product yield is high, the purification is easy, the requirements of pharmacopoeia impurity reference substances are met, a research foundation can be provided for zoledronic acid medicine toxicology, and a basis is provided for zoledronic acid medicine safety research.
Description
Technical Field
The invention belongs to the field of medicines, and in particular relates to a 2-position and 4-position alkyl substituted compound of an anti-osteoporosis drug zoledronic acid and a preparation method thereof.
Background
Osteoporosis (Osteoporosis) is a systemic disease that is prone to fracture due to reduced bone mass and bone density, damaged bone microstructure, and increased bone fragility. The spinal deformity and fracture disability can be caused when serious, the pain caused by the patient with limited movement reduces the life quality of the patient, makes the personal life difficult to self-care, and brings heavy burden to families and society. Bisphosphonates (BPs) can be adsorbed on hydroxyapatite crystals in bones to concentrate in bones, stay in cytoplasm after being ingested by osteoclasts, competitively inhibit the activity of the osteoclasts, and block pathological osteolysis, thereby achieving the effects of preventing and treating bone destruction.
Zoledronate (Zoledronate) is a third generation bisphosphonate drug developed by North Switzerland. For treating osteoporosis, the bone resorption resistance is 2 ten thousand times that of the first generation bisphosphonate etidronate sodium. In addition, the traditional Chinese medicine composition has wide clinical curative effects on various primary malignant tumors, and has the advantages of short administration time, small administration dosage, good curative effect, good patient tolerance and the like, and has wide market application prospect. The chemical structure of the active ingredients is shown as follows.
2 disubstituted impurities (A, B) are included in the European pharmacopoeia EP10.1 and define corresponding quality standards wherein impurity A does not exceed 0.10% and impurity B does not exceed 0.5%. The impurity A, B belongs to the technical impurity, has important influence on the safety and effectiveness of medicines, and has the chemical structure shown as follows.
According to literature reports, imidazole is used as a starting material in the existing zoledronic acid synthesis process, and is obtained through substitution, hydrolysis and phosphorylation reactions, so that in view of the influence of impurities on the quality of medicines, the medicine monitoring department pays more and more attention to the process, and the careful study on the starting materials used in the process becomes a necessary requirement for medicine research and development. Through literature search, 2-methylimidazole and 4-methylimidazole are contained in imidazole in the group standard T/CSPSTC 31-2019 'imidazole product test method and technical requirement', 2 impurities can be actually detected in imidazole, and 2-methyl/4-methyl substituted impurities A and B are possibly further formed in the synthesis process of zoledronic acid. The derivative impurities have not been reported, so that the method for synthesizing the derivative impurities is necessary to be studied. The impurity structure and synthetic route are shown below.
Disclosure of Invention
The invention provides an impurity of zoledronic acid for the first time, which is a new compound, belongs to process impurities formed by introducing starting materials, can provide a research foundation for the toxicology of zoledronic acid medicine and provides a basis for the safety research of zoledronic acid medicine.
The compound disclosed by the invention has the following structural characteristics:R 1 selected from H or-CH 3 ；R 2 Selected from H or-CH 3 And R is 1 、R 2 Not simultaneously H; r is R 3 Selected from-CH 2 COO - or-CH 2 C(OH)(PO 3 H 2 ) 2 。
Preferably, the compound has the structure:
the invention also provides a preparation method of the compound shown in the formula 1, which comprises the following steps:
(1) The starting material SM is subjected to substitution reaction with ethyl bromoacetate in a solvent in the presence of an acid binding agent to obtain a compound I,
(2) The compound I is secondarily substituted with ethyl bromoacetate in a solvent to obtain a compound II,
(3) The compound II is hydrolyzed at high temperature, ethanol molecules are removed, the system is extracted, concentrated and added with organic solvent for crystallization to obtain a compound III,
(4) In the presence of phosphorous acid, the compound III and phosphorus trichloride are subjected to phosphorylation reaction, and then the compound IV is obtained by hydrolysis of hydrochloric acid solution, decolorization, filtration and concentration and methanol addition,
R 1 selected from H or-CH 3 ；R 2 Selected from H or-CH 3 The method comprises the steps of carrying out a first treatment on the surface of the And R is 1 、R 2 Not simultaneously H; r is R 3 Selected from-CH 2 COO - or-CH 2 C(OH)(PO 3 H 2 ) 2 。
Step (4) the ratio of the compound III, the phosphorous acid and the phosphorus trichloride can be adjusted to control the product IV, and when the compound III is in excess relative to the phosphorous acid, the product isWhen phosphorous acid is in excess relative to compound III, the product is +.>One specific example of the present invention is as follows:
wherein n represents a compound name subscript, a or b.
Subscript a, which represents that a group R1 in the compound is methyl and a group R2 is a hydrogen atom; subscript b indicates that in the compound, the group R1 is a hydrogen atom and the group R2 is a methyl group.
(1) Preparation of Compounds I-n
After SM-n is dissolved in a corresponding solvent, an acid binding agent is added to react with ethyl bromoacetate at room temperature, after the reaction is finished, filtering is carried out, filtrate is washed by saturated saline, and an organic phase is recovered and concentrated under reduced pressure to obtain a compound I-n;
(2) Preparation of Compounds II-n
Dissolving the compound I-n in a corresponding solvent, reacting with ethyl bromoacetate under the condition of heating reflux, filtering after the reaction is finished, leaching a filter cake, and drying to obtain a compound II-n;
(3) Preparation of Compounds III-n
Dissolving the compound II-n in water, carrying out reflux reaction until the raw materials are completely reacted, adding dichloromethane for extraction, collecting a water layer, concentrating the water layer under reduced pressure, adding an organic solvent for crystallization, filtering and drying to obtain the compound III-n;
(4) Preparation of Compounds IV-n
After the compound III-n and the phosphorous acid are dissolved in the corresponding solvents, adding the phosphorus trichloride after heating, and stirring for reaction. Then pouring out the solvent, adding concentrated hydrochloric acid into the reaction system, and heating for hydrolysis reaction. And (3) adding active carbon for decoloring after the reaction is finished, cooling, filtering, concentrating a water layer under reduced pressure until the water layer is dried, adding methanol, and stirring to separate out to obtain the compound IV-n.
(5) Preparation of Compounds V-n
And (3) operating according to the step (4), and changing the charging equivalent of phosphorous acid and phosphorus trichloride to obtain a compound V-n.
Preferably, the solvent in the step (1) may be one or more of toluene, methyltetrahydrofuran, dichloromethane, chloroform and carbon tetrachloride, and more preferably dichloromethane.
Preferably, the acid-binding agent in the step (1) may be one or more of anhydrous potassium carbonate, anhydrous sodium carbonate, sodium hydroxide and potassium hydroxide, and more preferably, anhydrous potassium carbonate.
Preferably, the molar ratio of starting material SM-n to ethyl bromoacetate in step (1) is 1: (0.5-1.0), more preferably 1:0.9.
preferably, the solvent in the step (2) may be one or more of toluene, acetone, dichloromethane and chloroform, and more preferably acetone.
Preferably, the molar ratio of compound I-n to ethyl bromoacetate in step (2) is 1: (1.0-2.0), more preferably 1:1.2.
preferably, the solvent in the step (4) is one or more of benzene, toluene, xylene, chlorobenzene, dimethyl sulfoxide and sulfolane, and more preferably chlorobenzene.
Preferably, the molar ratio of the compound III, phosphorous acid and phosphorus trichloride in the step (4) is 1: (1.0-2.0): (1.0-2.0), more preferably 1:1.0:1.0.
Preferably, the molar ratio of the compound III-n, phosphorous acid and phosphorus trichloride in the step (5) is 1: (10-20): (10-20), more preferably 1:10:20.
In summary, the invention has the following beneficial effects:
the invention discovers a new impurity of zoledronic acid, which can provide a research basis for the toxicology of zoledronic acid medicine and a basis for the safety research of zoledronic acid medicine.
The invention provides an impurity reference substance which has the advantages of simple synthesis method, easily controlled conditions, high production safety, high product yield, easy purification and meeting pharmacopoeia requirements for the zoledronic acid impurity.
Detailed Description
The invention is further described in connection with the following detailed description:
example 1:
(1) Preparation of ethyl 2-methylimidazole acetate (I-a)
Into a 2L three-necked flask, 90g of 2-methylimidazole (1.1 mol) and 900mL of methylene chloride were added and dissolved under stirring, followed by 303.5g of anhydrous potassium carbonate (2.2 mol) and stirring for 15 minutes, and 173.9g of ethyl bromoacetate (1.04 mol) was added dropwise under control of the system temperature of 0 to 20 ℃. After dripping, the temperature is raised to 20-30 ℃ for reaction for 3 hours. Filtering, adding saturated sodium chloride into the filtrate for washing, combining organic phases, and evaporating low-boiling substances under reduced pressure to obtain 91g of brownish red oily matter, wherein the yield is 52%.
(2) Preparation of 1, 3-bis (2-ethoxy-2-oxoethyl) -2-methyl-1H-imidazol-3-ium (II-a)
To a 2L three-necked flask, 90g of ethyl 2-methylimidazole acetate (0.54 mol) and 900mL of acetone were added and dissolved with stirring, the mixture was warmed to reflux, and then 108.4g of ethyl bromoacetate (0.65 mol) was added and the reaction was stirred for 3 hours. The mixture was then cooled to room temperature and filtered, and the filter cake was washed with 180mL of acetone. The filter cake was dried under reduced pressure at 50℃to give 98g of a white powder in 54% yield.
(3) Preparation of 2- (1- (carboxymethyl) -2-methyl-1H-imidazol-3-ium-3-yl) acetic acid (III-a)
180mL of purified water and 90g of 1, 3-bis (2-ethoxy-2-oxyethyl) -2-methyl-1H-imidazol-3-ium were sequentially added to a 500mL three-necked flask, and the mixture was heated to 95-100℃with stirring and then refluxed for 8 hours. Cooling to room temperature, adding 180mL of dichloromethane to extract the reaction system for 2 times, collecting a water layer, concentrating the water layer at 60 ℃ under reduced pressure to remove 2/3 volume of solvent, adding 360mL of acetone into the concentrate, and stirring at room temperature to crystallize for 2h. The system was filtered, 100mL of acetone was used to rinse the filter cake, and the filter cake was dried under reduced pressure at 60℃to give 42g of white powder with a yield of 78.9%.
(4) Preparation of 2- (1- (2-hydroxy-2, 2-biphosphate ethyl) -2-methyl-1H-imidazol-3-ium-3-yl) acetate (IV-a)
40g of 2- (1- (carboxymethyl) -2-methyl-1H-imidazol-3-ium-3-yl) acetic acid (0.2 mol), 200mL of chlorobenzene, 16.5g of phosphorous acid (0.2 mol) were successively added to a 1L three-necked flask, and the temperature was raised to 100℃with stirring. 27.7g of phosphorus trichloride (0.2 mol) was added dropwise to the system, and the reaction was carried out with stirring at a constant temperature for 3 hours. Then cooling to 80 ℃, pouring out chlorobenzene, adding 280mL of concentrated hydrochloric acid, and keeping the temperature of 80-90 ℃ for continuous reaction for 3 hours. 4g of active carbon is added into the reaction system, the temperature is kept for decoloration for 30min, insoluble matters are removed by filtration, the filtrate is concentrated to be dry at 70 ℃, 400mL of methanol is slowly poured into the concentrate, the mixture is stirred and crystallized for 1h at room temperature, the filtration is carried out, and the filter cake is dried under reduced pressure at 70 ℃ to obtain 51g of white powder with the yield of 73.4 percent. ESI-MS [ M+H ] + ]345.02， 1 HNMR(500MHz,DMSO-d 6 )δ6.62(d,J＝7.5Hz,1H),6.42(d,J＝7.5Hz,1H),6.14(s,2H),5.19(s,1H),4.36(s,2H),2.31(s,3H)。
(5) Preparation of 1, 3-bis (2-hydroxy-2, 2-diphosphinoethyl) -2-methyl-1H-imidazol-3-ium (V-a)
40g of 2- (1- (carboxymethyl) -2-methyl-1H-imidazol-3-ium-3-yl) acetic acid (0.2 mol), 200mL of chlorobenzene, 165.5g of phosphorous acid (2 mol) were successively added to a 2L three-necked flask, and the temperature was raised to 100℃with stirring. 554.4g of phosphorus trichloride (4 mol) was added dropwise to the system, and the reaction was carried out with stirring at a constant temperature for 3 hours. The chlorobenzene was decanted, 400mL of concentrated hydrochloric acid was added, and the reaction was continued for 3 hours at 90-100 ℃.4g of active carbon is added into the reaction system, the temperature is kept for decoloration for 30min, insoluble matters are removed by filtration, the filtrate is concentrated to be dry at 70 ℃, 400mL of methanol is slowly poured into the concentrate, the mixture is stirred and crystallized for 1h at room temperature, the filtration is carried out, and the filter cake is dried under reduced pressure at 70 ℃ to obtain 64.5g of white powder, and the yield is 65%. ESI-MS [ M-H ] + ]490.98， 1 H NMR(500MHz,DMSO-d 6 )δ6.52(s,1H),6.14(s,2H),5.07(s,1H),4.36(s,2H),2.38(s,3H)。
Example 2:
(1) Preparation of ethyl 4-methylimidazole acetate (I-b)
To a 2L three-necked flask, 90g of 4-methylimidazole (1.1 mol) and 900mL of methyltetrahydrofuran were added and dissolved under stirring, followed by adding 61.5g of potassium hydroxide (1.1 mol) and 151.5g of anhydrous potassium carbonate (1.1 mol), stirring for 15 minutes, and dropwise adding 128.1g of ethyl bromoacetate (0.7 mol) at a temperature of 0 to 20 ℃. After dripping, the temperature is raised to 20-30 ℃ for reaction for 6 hours. The mixture was filtered and the filter cake was washed with 180mL of methyltetrahydrofuran. The combined filtrates were washed with saturated sodium chloride, the organic phase was collected, and the solvent was distilled off under reduced pressure to give 94g of brown oil with a yield of 72.8%.
(2) Preparation of 1, 3-bis (2-ethoxy-2-oxoethyl) -4-methyl-1H-imidazol-3-ium (II-b)
80g of ethyl 4-methylimidazole acetate (0.47 mol) and 800mL of toluene were added to a 2L three-necked flask and dissolved with stirring, the mixture was warmed to reflux, and then 119.1g of ethyl bromoacetate (0.71 mol) was added thereto, followed by stirring for 16 hours. Then cooled to room temperature, filtered and the filter cake was washed with 160mL toluene. The filter cake was dried under reduced pressure at 50℃to give 102g of a white powder in 63.9% yield.
(3) Preparation of 2- (1- (carboxymethyl) -4-methyl-1H-imidazol-3-ium-3-yl) acetic acid (III-b)
180mL of purified water and 90g of 1, 3-bis (2-ethoxy-2-oxyethyl) -4-methyl-1H-imidazol-3-ium were sequentially added to a 500mL three-necked flask, and the mixture was heated to 95-100℃with stirring and then refluxed for 8 hours. The reaction system was concentrated to dryness under reduced pressure at 60℃and then 360mL of acetone was added to the concentrate, followed by crystallization under stirring at room temperature for 2 hours. The system was filtered, 100ml acetone was used to rinse the filter cake, and the filter cake was dried under reduced pressure at 60℃to give 33g of white powder with a yield of 62%.
(4) Preparation of 2- (1- (2-hydroxy-2, 2-biphosphate ethyl) -4-methyl-1H-imidazol-3-ium-3-yl) acetate (IV-b)
40g of 2- (1- (carboxymethyl) -4-methyl-1H-imidazol-3-ium-3-yl) acetic acid (0.2 mol), 200mL of sulfolane, 19.8g of phosphorous acid (0.24 mol) were successively added to a 1L three-necked flask, and the temperature was raised to 100℃with stirring. 41.6g of phosphorus trichloride (0.3 mol) was added dropwise to the system, and the reaction was carried out with stirring at a constant temperature for 4 hours. The solution was then poured off, 280mL of concentrated hydrochloric acid was added, and the reaction was continued at 100℃for 3 hours. 4g of active carbon is added into the reaction system, the temperature is kept for decoloration for 30min, insoluble matters are removed by filtration, the filtrate is concentrated to be dry at 70 ℃, 400mL of methanol is slowly poured into the concentrate, stirring crystallization is carried out at room temperature for 1h, filtration is carried out, and the filter cake is dried under reduced pressure at 70 ℃ to obtain 31g of white powder, and the yield is 44.6%. ESI-MS [ M+H ] + ]345.11， 1 H NMR(500MHz,DMSO-d 6 )δ6.64(s,1H),6.15(s,2H),4.79(s,1H),4.37(s,2H),3.93(s,1H),2.29(s,3H)。
(5) Preparation of 1, 3-bis (2-hydroxy-2, 2-diphosphinoethyl) -4-methyl-1H-imidazol-3-ium (V-b)
40g of 2- (1- (carboxymethyl) -4-methyl-1H-imidazol-3-ium-3-yl) acetic acid (0.2 mol), 400mL of dimethyl sulfoxide, 215.1g of phosphorous acid (2.6 mol) were successively added to a 2L three-necked flask, and the temperature was raised to 100℃with stirring. 471.2g of phosphorus trichloride (3.4 mol) was added dropwise to the system, and the reaction was carried out with stirring at a constant temperature for 5 hours. The solution was decanted, 400mL of concentrated hydrochloric acid was added, and the reaction was continued at 100deg.C for 3h. Adding 4g active carbon to the reaction system for decolorizing for 30min, filtering to remove insoluble substances, concentrating the filtrate at 70deg.C to dryness, slowly pouring 400mL methanol into the concentrate, and cooling to room temperatureStirring and crystallizing for 1h, filtering, and drying the filter cake under reduced pressure at 70 ℃ to obtain 35g of white powder with the yield of 35.3%. ESI-MS [ M-H ] + ]490.12， 1 H NMR(500MHz,DMSO-d 6 )δ6.26(s,1H),5.66(s,2H),5.06(s,1H),4.36(s,2H),2.74(s,1H),2.32(s,3H)。
Claims (10)
1. A compound characterized by having the structure of formula 1:
wherein R is 1 Selected from H or-CH 3 ；R 2 Selected from H or-CH 3 And R is 1 、R 2 Not simultaneously H; r is R 3 Selected from-CH 2 COO - or-CH 2 C(OH)(PO 3 H 2 ) 2 。
2. The compound according to claim 1, wherein R 1 Selected from-CH 3 ；R 2 Selected from H; or R is 1 Selected from H; r is R 2 Selected from-CH 3 。
3. A process for the preparation of a compound of formula 1 according to claim 1 or 2, comprising the steps of:
(1) The starting material SM is subjected to substitution reaction with ethyl bromoacetate in a solvent in the presence of an acid binding agent to obtain a compound I,
(2) The compound I is secondarily substituted with ethyl bromoacetate in a solvent to obtain a compound II,
(3) The compound II is hydrolyzed at high temperature, ethanol molecules are removed, the system is extracted, concentrated and added with organic solvent for crystallization to obtain a compound III,
(4) In the presence of phosphorous acid, the compound III and phosphorus trichloride are subjected to phosphorylation reaction, and then the compound IV is obtained by hydrolysis of hydrochloric acid solution, decolorization, filtration and concentration and methanol addition,
R 1 selected from H or-CH 3 ，R 2 Selected from H or-CH 3 And R is 1 、R 2 Not simultaneously H; r is R 3 Selected from-CH 2 COO - or-CH 2 C(OH)(PO 3 H 2 ) 2 。
4. The process according to claim 3, wherein the solvent in the reaction step (1) is one or more selected from toluene, methyltetrahydrofuran, methylene chloride, chloroform and carbon tetrachloride.
5. The process according to claim 3, wherein the acid-binding agent in the reaction step (1) is one or more selected from the group consisting of anhydrous potassium carbonate, anhydrous sodium carbonate, sodium hydroxide and potassium hydroxide.
6. A process according to claim 3, characterized in that the molar ratio of starting material SM to ethyl bromoacetate in reaction step (1) is 1: (0.5-1.0).
7. The process according to claim 3, wherein the solvent in the step (2) is one or more selected from toluene, acetone, methylene chloride and chloroform.
8. A process according to claim 3, characterized in that the molar ratio of compound I to ethyl bromoacetate in reaction step (2) is 1: (1.0-2.0).
9. The process according to claim 3, wherein the solvent in the step (4) is one or more selected from benzene, toluene, xylene, chlorobenzene, dimethylsulfoxide, sulfolane.
10. The preparation method according to claim 3, wherein the molar ratio of the compound III to the phosphorous acid and the phosphorus trichloride in the reaction step (4) is 1: (1.0-2.0): (1.0-2.0), R 3 is-CH 2 COO - The method comprises the steps of carrying out a first treatment on the surface of the The molar ratio of the compound III to the phosphorous acid and the phosphorus trichloride is 1: (10-20): (10-20), R 3 is-CH 2 C(OH)(PO 3 H 2 ) 2 。
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