CN113968820A - 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride compound and preparation method thereof - Google Patents
1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride compound and preparation method thereof Download PDFInfo
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- -1 (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride Chemical compound 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- IPWKIXLWTCNBKN-UHFFFAOYSA-N Madelen Chemical compound CC1=NC=C([N+]([O-])=O)N1CC(O)CCl IPWKIXLWTCNBKN-UHFFFAOYSA-N 0.000 claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 16
- 238000004519 manufacturing process Methods 0.000 claims abstract description 10
- 239000012535 impurity Substances 0.000 claims abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 47
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- 239000007787 solid Substances 0.000 claims description 32
- 238000001914 filtration Methods 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 21
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- 239000000706 filtrate Substances 0.000 claims description 13
- 239000007791 liquid phase Substances 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 11
- 238000010791 quenching Methods 0.000 claims description 11
- FFYTTYVSDVWNMY-UHFFFAOYSA-N 2-Methyl-5-nitroimidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1 FFYTTYVSDVWNMY-UHFFFAOYSA-N 0.000 claims description 10
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical group Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-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
- 239000003054 catalyst Substances 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- 235000017550 sodium carbonate Nutrition 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical group [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 5
- 229940090181 propyl acetate Drugs 0.000 claims description 5
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 5
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 4
- 238000004587 chromatography analysis Methods 0.000 claims description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 4
- 239000012071 phase Substances 0.000 claims description 4
- 239000011736 potassium bicarbonate Substances 0.000 claims description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical group Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 3
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000011592 zinc chloride Chemical group 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000001514 detection method Methods 0.000 claims description 2
- 238000010828 elution Methods 0.000 claims description 2
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical compound CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- 239000000741 silica gel Substances 0.000 claims description 2
- 229910002027 silica gel Inorganic materials 0.000 claims description 2
- 229960002313 ornidazole Drugs 0.000 abstract description 16
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 238000009833 condensation Methods 0.000 abstract description 3
- 230000005494 condensation Effects 0.000 abstract description 3
- 230000002349 favourable effect Effects 0.000 abstract description 2
- 239000010410 layer Substances 0.000 description 30
- 239000000203 mixture Substances 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 18
- 238000005406 washing Methods 0.000 description 18
- 239000000047 product Substances 0.000 description 10
- 235000015110 jellies Nutrition 0.000 description 9
- 239000008274 jelly Substances 0.000 description 9
- 239000002245 particle Substances 0.000 description 9
- 238000004237 preparative chromatography Methods 0.000 description 9
- 238000004537 pulping Methods 0.000 description 9
- 238000001816 cooling Methods 0.000 description 6
- YZEUHQHUFTYLPH-UHFFFAOYSA-N 2-nitroimidazole Chemical compound [O-][N+](=O)C1=NC=CN1 YZEUHQHUFTYLPH-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 3
- 229960000282 metronidazole Drugs 0.000 description 3
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- HJLSLZFTEKNLFI-UHFFFAOYSA-N Tinidazole Chemical compound CCS(=O)(=O)CCN1C(C)=NC=C1[N+]([O-])=O HJLSLZFTEKNLFI-UHFFFAOYSA-N 0.000 description 2
- 208000022506 anaerobic bacteria infectious disease Diseases 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229960005053 tinidazole Drugs 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000004957 nitroimidazoles Chemical class 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/91—Nitro radicals
- C07D233/92—Nitro radicals attached in position 4 or 5
- C07D233/94—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to other ring members
Abstract
The invention discloses a 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride compound and a preparation method thereof, wherein the molecular formula of the compound is as follows: c10H16Cl3N3O4(ii) a Structural formula (xvi):
Description
Technical Field
The invention relates to the technical field of compounds and compound synthesis, in particular to a 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride compound and a preparation method thereof.
Background
Ornidazole (Ornidazole), a third generation nitroimidazole drug, is mainly used for preventing and treating anaerobic bacterial infection.
Ornidazole was first developed successfully by hoffer.m et al, usa, and was patented 5/25/1969. Then Hoffman et al assigned to Hoffmann-LaRocheandCo, Switzerland, Roche, in 1977-. Tiberal injection marketed in france by roche in 2004, with a specification of 0.5 g: 3ml and 1 g: 6ml, was also marketed by Roche in Switzerland in 2007. However, for various reasons, Roche, the original research enterprise, has not yet marketed the variety in China.
Ornidazole is a 40-billion-element large-variety nitroimidazole medicament, and is mainly used for preventing and treating anaerobic bacterial infection. Nitroimidazoles are the main species in the field of treatment of anaerobic infections, and the research on such drugs has undergone the third generation of development, first, second and third generation of metronidazole, starting in the 60 th of the 20 th century. In 2010-2014, the dosage amount of the nitroimidazole preparation in China generally increases from 55.81 billion yuan in 2010 to 64.10 billion yuan in 2014. Because the ornidazole products are higher in safety than metronidazole and tinidazole, the ornidazole products are rapidly increased after being marketed as substitute products of metronidazole and tinidazole, and according to data of southern medical and economic research institute, the ornidazole occupies 55.63% of nitroimidazole drug markets in 2014, and the ornidazole products have absolute advantages in the markets.
Since 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride is an impurity compound which is easily generated in a condensation step in the synthesis process of ornidazole and has a large conversion rate in the impurity, more research on the compound is needed.
Disclosure of Invention
Based on the defects of the prior art, the technical problem solved by the invention is to determine the information of the name, molecular formula, structural formula, molecular weight, mass-to-charge ratio (m/z), element proportion and the like of the impurity 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride in ornidazole and a preparation method of the compound.
In order to solve the above technical problems, the present invention provides a 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride compound, which is as follows:
name: 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazolium chloride;
the molecular formula is as follows: c10H16Cl3N3O4；
Structural formula (xvi):
molecular weight: 348.6, respectively;
mass to charge ratio (m/z): 347.02, respectively;
element proportion: c, 34.45%; h, 4.63%; cl, 30.51%; n, 12.05%; and O, 18.36 percent.
A method for preparing 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride compound as described above, according to the following reaction equation:
alternatively, the first and second electrodes may be,
comprises the following steps:
(1) adding a catalyst b into a solvent a, then adding a main substance c and epoxy chloropropane, stirring for reaction, then adding water for quenching, and layering; the main substance c is 1- (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole (ornidazole) or 2-methyl-5-nitroimidazole;
(2) taking out the water layer layered in the step (1), extracting with a solvent a to remove impurities, and leaving the water layer;
(3) adjusting the pH value of the water layer obtained in the step (2) to 5.5-7.5 by using alkali d, adding a solvent e, stirring, and then filtering;
(4) taking the filtrate obtained by filtering in the step (3), concentrating under reduced pressure at the temperature of below 60 ℃ until the filtrate is dry, adding water for dissolving, taking out, and collecting main components through a preparation chromatography;
(5) concentrating the main components collected in the step (4) at a temperature below 60 ℃ under reduced pressure until the main components are dried, then adding a solvent f, stirring, filtering to obtain a white solid, and drying to obtain a compound of 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride;
wherein, according to the weight ratio, the solvent a: catalyst b: main substance c: solvent e: and (3) the solvent f is 6-15: 1.3-2.0: 1: 1-3: 1 to 3.
As a preferred aspect of the above technical solution, the method for preparing a 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride compound according to the present invention further comprises some or all of the following technical features:
as an improvement of the technical scheme, the reaction temperature condition of the step (1) is-10-70 ℃, and the preferable temperature is 0-10 ℃.
As an improvement of the technical scheme, the solvent a is ethyl acetate, propyl acetate, butyl acetate or dichloromethane, and the preferable solvent is ethyl acetate or propyl acetate.
As an improvement of the technical scheme, the catalyst b is aluminum trichloride, ferric trichloride or zinc chloride, and the preferred catalyst is aluminum trichloride.
As an improvement of the technical scheme, the alkali d is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, and preferably, the alkali is sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.
As an improvement of the technical scheme, the solvent e is methanol, tetrahydrofuran or acetone, and preferably the solvent is methanol.
As an improvement of the above technical scheme, f is ethanol, isopropanol or butanol, and preferably the solvent is ethanol.
As an improvement of the technical scheme, the preparation chromatography in the step (4) is a binary high-pressure liquid phase preparation method.
As an improvement of the above technical scheme, the binary high-pressure liquid phase preparation method specifically comprises the following steps:
a chromatographic column: One-3025-10-C18 silica gel column;
detection wavelength: 254 nm;
flow rate: 24 ml/min;
mobile phase A: methanol;
mobile phase B: 0.1% aqueous acetic acid;
elution gradient:
| time (min) | A％ | B％ |
| 0 | 90 | 10 |
| 10 | 90 | 10 |
| 10.3 | 60 | 45 |
| 20 | 60 | 45 |
| 20.3 | 90 | 10 |
| 30 | 90 | 10 |
。
Compared with the prior art, the technical scheme of the invention has the following beneficial effects: in the synthesis process of ornidazole, 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride is an impurity compound which is easy to generate in a condensation step, and the impurity compound has a high conversion rate, so that the intensive research on the compound is favorable for the production control of ornidazole.
The foregoing description is only an overview of the technical solutions of the present invention, and in order to make the technical means of the present invention more clearly understood, the present invention may be implemented in accordance with the contents of the description, and in order to make the above and other objects, features, and advantages of the present invention more clearly understood, the following detailed description is given in conjunction with the preferred embodiments.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings of the embodiments will be briefly described below.
FIG. 1 is a mass spectrum of the product of example 1;
FIG. 2 is a NMR spectrum of a product obtained in example 1;
FIG. 3 is a NMR spectrum of the product of example 1 after exchange of deuterated water.
Detailed Description
Other aspects, features and advantages of the present invention will become apparent from the following detailed description, which, when taken in conjunction with the drawings, illustrate by way of example the principles of the invention.
Target compound:
1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride compound:
name: 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazolium chloride;
the molecular formula is as follows: c10H16Cl3N3O4；
Structural formula (xvi):
molecular weight: 348.6, respectively;
mass to charge ratio (m/z): 347.02, respectively;
element proportion: c, 34.45%; h, 4.63%; cl, 30.51%; n, 12.05%; and O, 18.36 percent.
Example 1
Preparation of 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride:
80ml of ethyl acetate are added into a clean 250ml three-neck flask, stirring and cooling are started, and 12.7g of aluminum trichloride is slowly added. After the addition, the mixture was stirred until no solid particles were evident, and 10g of 2-methyl-5-nitroimidazole was added. And then slowly dripping 65.8g of epoxy chloropropane, and controlling the temperature in the reaction flask to be-10 ℃ in the process. After the dropwise addition, the temperature is kept between 10 ℃ below zero and 10 ℃ below zero for reaction for 3 hours. After the reaction, 60ml of water was added to quench, and then the mixture was allowed to stand for layering, and the aqueous layer was separated and the organic layer was discarded. Extracting the water layer with ethyl acetate 20ml x 2, discarding the extracted organic layer, adjusting pH of the water layer to 5.5 with sodium hydroxide, washing out a large amount of jelly, adding methanol 200ml, stirring, washing, and filtering; concentrating the filtrate at below 60 deg.C under reduced pressure to dry to obtain oil, dissolving in 50ml of water, separating by preparative chromatography (claim 10), collecting main peak component within 20min, concentrating at below 60 deg.C under reduced pressure to dry to obtain oil, pulping with 30ml of ethanol to separate out white solid, filtering, and drying to obtain solid 1.3g with liquid phase purity of 98.5%.
When the solid compound is detected, the molecular weight of the solid compound is 312.05 without chloride ions, the hydrogen number of nuclear magnetic resonance is 16, the hydrogen number of nuclear magnetic resonance after deuterium-substituted water exchange is 14, and the properties of the solid compound are consistent with the properties of the compound 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride.
FIG. 1 is a mass spectrum of the product of example 1; FIG. 2 is a NMR spectrum of a product obtained in example 1; FIG. 3 is a NMR spectrum of the product of example 1 after exchange of deuterated water.
Example 2
Preparation of 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride:
80ml of propyl acetate are added into a clean 250ml three-necked flask, stirring is started and the temperature is reduced, and 12.7g of ferric trichloride is slowly added. After the addition, the mixture was stirred until no solid particles were evident, and 10g of 2-methyl-5-nitroimidazole was added. And then slowly dripping 65.8g of epoxy chloropropane, and controlling the temperature in the reaction flask to be 10-30 ℃ in the process. After the dropwise addition, the temperature is kept at 10-30 ℃ for reaction for 3 h. After the reaction, 60ml of water was added to quench, and then the mixture was allowed to stand for layering, and the aqueous layer was separated and the organic layer was discarded. Extracting the water layer with propyl acetate 20ml x 2, discarding the extracted organic layer, adjusting pH of the water layer to 6.0 with potassium hydroxide, washing out a large amount of jelly, adding tetrahydrofuran 200ml, stirring, washing, and filtering; concentrating the filtrate at below 60 deg.C under reduced pressure to dry to obtain oil, dissolving in 50ml of water, separating by preparative chromatography (claim 10), collecting main peak component within 20min, concentrating at below 60 deg.C under reduced pressure to dry to obtain oil, pulping with 30ml of isopropanol to separate out white solid, filtering, and drying to obtain solid 1.5g with liquid phase purity of 98.7%.
Example 3
Preparation of 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride:
80ml of butyl acetate are added into a clean 250ml three-necked flask, stirring is started and the temperature is reduced, and 12.7g of zinc chloride is slowly added. After the addition, the mixture was stirred until no solid particles were evident, and 10g of 2-methyl-5-nitroimidazole was added. And then slowly dropwise adding 65.8g of epoxy chloropropane, and controlling the temperature in the reaction flask to be 30-50 ℃ in the process. After the dropwise addition, the temperature is kept at 30-50 ℃ for reaction for 3 h. After the reaction, 60ml of water was added to quench, and then the mixture was allowed to stand for layering, and the aqueous layer was separated and the organic layer was discarded. Extracting the water layer with butyl acetate 20ml x 2, discarding the extracted organic layer, adjusting pH of the water layer to 6.5 with sodium carbonate, washing out a large amount of jelly, adding acetone 200ml, stirring, washing, and filtering; concentrating the filtrate at below 60 deg.C under reduced pressure to dry to obtain oil, dissolving in 50ml of water, separating by preparative chromatography (claim 10), collecting main peak component within 20min, concentrating at below 60 deg.C under reduced pressure to dry to obtain oil, pulping with 30ml of butanol, precipitating white solid, filtering, and drying to obtain solid 1.2g with liquid phase purity of 98.8%.
Example 4
Preparation of 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride:
80ml of dichloromethane is added into a clean 250ml three-neck flask, stirring is started, the temperature is reduced, and 12.7g of aluminum trichloride is slowly added. After the addition, the mixture was stirred until no solid particles were evident, and 10g of 2-methyl-5-nitroimidazole was added. And then slowly dripping 65.8g of epoxy chloropropane, and controlling the temperature in the reaction flask to be 50-70 ℃ in the process. After the dropwise addition, the temperature is kept between 50 and 70 ℃ for reaction for 3 hours. After the reaction, 60ml of water was added to quench, and then the mixture was allowed to stand for layering, and the aqueous layer was separated and the organic layer was discarded. Extracting the water layer with dichloromethane 20ml x 2, discarding the extracted organic layer, adjusting pH of the water layer to 7.0 with potassium carbonate, washing out a large amount of jelly, adding methanol 200ml, stirring, washing, and filtering; concentrating the filtrate at below 60 deg.C under reduced pressure to dry to obtain oil, dissolving in 50ml of water, separating by preparative chromatography (claim 10), collecting main peak component within 20min, concentrating at below 60 deg.C under reduced pressure to dry to obtain oil, pulping with 30ml of ethanol to separate out white solid, filtering, and drying to obtain solid 1.7g with liquid phase purity of 98.3%.
Example 5
Preparation of 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride:
80ml of ethyl acetate are added into a clean 250ml three-neck flask, stirring and cooling are started, and 12.7g of aluminum trichloride is slowly added. After the addition, the mixture was stirred until no solid particles were evident, and 10g of 1- (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole (ornidazole) was added. And then slowly dropwise adding 32.9g of epoxy chloropropane, and controlling the temperature in the reaction flask to be 0-10 ℃ in the process. After the dropwise addition, the temperature is kept between 0 and 10 ℃ for reaction for 3 hours. After the reaction, 60ml of water was added to quench, and then the mixture was allowed to stand for layering, and the aqueous layer was separated and the organic layer was discarded. Extracting the water layer with ethyl acetate 20ml x 2, discarding the extracted organic layer, adjusting pH of the water layer to 7.5 with sodium bicarbonate, washing out a large amount of jelly, adding methanol 200ml, stirring, washing, and filtering; concentrating the filtrate at below 60 deg.C under reduced pressure to dry to obtain oil, dissolving in 50ml of water, separating by preparative chromatography (claim 10), collecting main peak component within 20min, concentrating at below 60 deg.C under reduced pressure to dry to obtain oil, pulping with 30ml of ethanol to separate out white solid, filtering, and drying to obtain solid 1.6g with liquid phase purity of 98.9%.
Example 6
Preparation of 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride:
80ml of ethyl acetate are added into a clean 250ml three-neck flask, stirring and cooling are started, and 12.7g of aluminum trichloride is slowly added. After the addition, the mixture was stirred until no solid particles were evident, and 10g of 2-methyl-5-nitroimidazole was added. And then slowly dropwise adding 65.8g of epoxy chloropropane, and controlling the temperature in the reaction flask to be 0-10 ℃ in the process. After the dropwise addition, the temperature is kept between 0 and 10 ℃ for reaction for 3 hours. After the reaction, 60ml of water was added to quench, and then the mixture was allowed to stand for layering, and the aqueous layer was separated and the organic layer was discarded. Extracting the water layer with ethyl acetate 20ml x 2, discarding the extracted organic layer, adjusting pH of the water layer to 6.5 with potassium bicarbonate, washing out a large amount of jelly, adding methanol 200ml, stirring, washing, and filtering; concentrating the filtrate at below 60 deg.C under reduced pressure to dry to obtain oil, dissolving in 50ml of water, separating by preparative chromatography (claim 10), collecting main peak component within 20min, concentrating at below 60 deg.C under reduced pressure to dry to obtain oil, pulping with 30ml of ethanol to separate out white solid, filtering, and drying to obtain solid 1.4g with liquid phase purity of 98.9%.
Example 7
Preparation of 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride:
80ml of ethyl acetate are added into a clean 250ml three-neck flask, stirring and cooling are started, and 12.7g of aluminum trichloride is slowly added. After the addition, the mixture was stirred until no solid particles were evident, and 10g of 2-methyl-5-nitroimidazole was added. And then slowly dropwise adding 65.8g of epoxy chloropropane, and controlling the temperature in the reaction flask to be 0-10 ℃ in the process. After the dropwise addition, the temperature is kept between 0 and 10 ℃ for reaction for 3 hours. After the reaction, 60ml of water was added to quench, and then the mixture was allowed to stand for layering, and the aqueous layer was separated and the organic layer was discarded. Extracting the water layer with ethyl acetate 20ml x 2, discarding the extracted organic layer, adjusting pH of the water layer to 6.5 with sodium carbonate, washing out a large amount of jelly, adding methanol 200ml, stirring, washing, and filtering; concentrating the filtrate at below 60 deg.C under reduced pressure to dry to obtain oil, dissolving in 50ml of water, separating by preparative chromatography (claim 10), collecting main peak component within 20min, concentrating at below 60 deg.C under reduced pressure to dry to obtain oil, pulping with 30ml of ethanol to separate out white solid, filtering, and drying to obtain solid 1.3g with liquid phase purity of 99.0%.
Example 8
Preparation of 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride:
80ml of ethyl acetate are added into a clean 250ml three-neck flask, stirring and cooling are started, and 12.7g of aluminum trichloride is slowly added. After the addition, the mixture was stirred until no solid particles were evident, and 10g of 2-methyl-5-nitroimidazole was added. And then slowly dropwise adding 65.8g of epoxy chloropropane, and controlling the temperature in the reaction flask to be 0-10 ℃ in the process. After the dropwise addition, the temperature is kept between 0 and 10 ℃ for reaction for 3 hours. After the reaction, 60ml of water was added to quench, and then the mixture was allowed to stand for layering, and the aqueous layer was separated and the organic layer was discarded. Extracting the water layer with ethyl acetate 20ml x 2, discarding the extracted organic layer, adjusting pH of the water layer to 6.5 with sodium carbonate, washing out a large amount of jelly, adding methanol 200ml, stirring, washing, and filtering; concentrating the filtrate at below 60 deg.C under reduced pressure to dry to obtain oil, dissolving in 50ml of water, separating by preparative chromatography (claim 10), collecting main peak component within 20min, concentrating at below 60 deg.C under reduced pressure to dry to obtain oil, pulping with 30ml of ethanol to separate out white solid, filtering, and drying to obtain solid 1.6g with liquid phase purity of 99.1%.
Example 9
Preparation of 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride:
80ml of ethyl acetate are added into a clean 250ml three-neck flask, stirring and cooling are started, and 12.7g of aluminum trichloride is slowly added. After the addition, the mixture was stirred until no solid particles were evident, and 10g of 2-methyl-5-nitroimidazole was added. And then slowly dropwise adding 65.8g of epoxy chloropropane, and controlling the temperature in the reaction flask to be 0-10 ℃ in the process. After the dropwise addition, the temperature is kept between 0 and 10 ℃ for reaction for 3 hours. After the reaction, 60ml of water was added to quench, and then the mixture was allowed to stand for layering, and the aqueous layer was separated and the organic layer was discarded. Extracting the water layer with ethyl acetate 20ml x 2, discarding the extracted organic layer, adjusting pH of the water layer to 6.5 with sodium carbonate, washing out a large amount of jelly, adding methanol 200ml, stirring, washing, and filtering; concentrating the filtrate at below 60 deg.C under reduced pressure to dry to obtain oil, dissolving in 50ml of water, separating by preparative chromatography (claim 10), collecting main peak component within 20min, concentrating at below 60 deg.C under reduced pressure to dry to obtain oil, pulping with 30ml of ethanol to separate out white solid, filtering, and drying to obtain solid 2.3g with liquid phase purity of 99.5%.
The raw materials listed in the invention, the upper and lower limits and interval values of the raw materials of the invention, and the upper and lower limits and interval values of the process parameters (such as temperature, time and the like) can all realize the invention, and the examples are not listed.
While the foregoing is directed to the preferred embodiment of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow.
Claims (10)
1. 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride compound characterized in that the compound is as follows:
name: 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazolium chloride;
the molecular formula is as follows: c10H16Cl3N3O4；
Structural formula (xvi):
molecular weight: 348.6, respectively;
mass to charge ratio (m/z): 347.02, respectively;
element proportion: c, 34.45%; h, 4.63%; cl, 30.51%; n, 12.05%; and O, 18.36 percent.
2. A method for preparing 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride compound according to claim 1, characterized by carrying out the reaction according to the following reaction equation:
alternatively, the first and second electrodes may be,
comprises the following steps:
(1) adding a catalyst b into a solvent a, then adding a main substance c and epoxy chloropropane, stirring for reaction, then adding water for quenching, and layering; the main substance c is 1- (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole or 2-methyl-5-nitroimidazole;
(2) taking out the water layer layered in the step (1), extracting with a solvent a to remove impurities, and leaving the water layer;
(3) adjusting the pH value of the water layer obtained in the step (2) to 5.5-7.5 by using alkali d, adding a solvent e, stirring, and then filtering;
(4) taking the filtrate obtained by filtering in the step (3), concentrating under reduced pressure at the temperature of below 60 ℃ until the filtrate is dry, adding water for dissolving, taking out, and collecting main components through a preparation chromatography;
(5) concentrating the main components collected in the step (4) at a temperature below 60 ℃ under reduced pressure until the main components are dried, then adding a solvent f, stirring, filtering to obtain a white solid, and drying to obtain a compound of 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride;
wherein, according to the weight ratio, the solvent a: catalyst b: main substance c: solvent e: and (3) the solvent f is 6-15: 1.3-2.0: 1: 1-3: 1 to 3.
3. The method for producing 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride compound according to claim 2, characterized in that: the reaction temperature condition of the step (1) is-10 ℃ to 70 ℃.
4. The method for producing 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride compound according to claim 2, characterized in that: the solvent a is ethyl acetate, propyl acetate, butyl acetate or dichloromethane.
5. The method for producing 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride compound according to claim 2, characterized in that: the catalyst b is aluminum trichloride, ferric trichloride or zinc chloride.
6. The method for producing 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride compound according to claim 2, characterized in that: the alkali d is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.
7. The method for producing 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride compound according to claim 2, characterized in that: the solvent e is methanol, tetrahydrofuran or acetone.
8. The method for producing 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride compound according to claim 2, characterized in that: and f is ethanol, isopropanol or butanol.
9. The method for producing 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride compound according to claim 2, characterized in that: the preparation chromatography in the step (4) is a binary high-pressure liquid phase preparation method.
10. The method for producing 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride compound according to claim 9, characterized in that: the binary high-pressure liquid phase preparation method specifically comprises the following steps:
a chromatographic column: One-3025-10-C18 silica gel column;
detection wavelength: 254 nm;
flow rate: 24 ml/min;
mobile phase A: methanol;
mobile phase B: 0.1% aqueous acetic acid;
elution gradient:
。
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| CN103130721A (en) * | 2013-03-01 | 2013-06-05 | 张若煜 | Ornidazole green synthetic method |
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| CN111471017A (en) * | 2020-06-28 | 2020-07-31 | 湖南九典宏阳制药有限公司 | Process for preparing 5-nitroimidazole drugs by using organic micromolecule catalysis |
| WO2021135980A1 (en) * | 2019-12-30 | 2021-07-08 | 重庆典索医药科技有限公司 | Solvent system capable of effectively dissolving ornidazole or levornidazole, and application thereof |
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| US20130202698A1 (en) * | 2005-07-08 | 2013-08-08 | Nanjing Sanhome Pharmaceutical Co., Ltd. | L-ornidazole formulations and their applications in treatment of parasitic infections |
| CN103130721A (en) * | 2013-03-01 | 2013-06-05 | 张若煜 | Ornidazole green synthetic method |
| CN105254569A (en) * | 2015-11-02 | 2016-01-20 | 山东齐都药业有限公司 | Preparation method of ornidazole injection impurity 1-(3-chloro-propenyl)-2-methyl-5-nitroimidazole |
| WO2021135980A1 (en) * | 2019-12-30 | 2021-07-08 | 重庆典索医药科技有限公司 | Solvent system capable of effectively dissolving ornidazole or levornidazole, and application thereof |
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