CN108409786A - A kind of industrialized preparing process of phosphoric acid l-ornidazole ester disodium hydrate - Google Patents
A kind of industrialized preparing process of phosphoric acid l-ornidazole ester disodium hydrate Download PDFInfo
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- CN108409786A CN108409786A CN201810138699.6A CN201810138699A CN108409786A CN 108409786 A CN108409786 A CN 108409786A CN 201810138699 A CN201810138699 A CN 201810138699A CN 108409786 A CN108409786 A CN 108409786A
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- phosphoric acid
- ornidazole
- ester disodium
- disodium hydrate
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Abstract
The invention belongs to technology of pharmaceutical engineering fields, and in particular to a kind of industrialized preparing process of phosphoric acid l-ornidazole ester disodium hydrate.The present invention is esterified with phosphorus oxychloride, using l-ornidazole as raw material after hydrolysis, with sodium hydroxide solution at sodium salt, then through being recrystallized to give phosphoric acid l-ornidazole ester disodium hydrate in organic solvent.Preparation method of the present invention is easy, and high income is suitable for industrialized production.
Description
Technical field
The invention belongs to technology of pharmaceutical engineering fields, are related to a kind of industrial metaplasia of phosphoric acid l-ornidazole ester disodium hydrate
Production method.
Background technology
Nitro glyoxaline antibacterials (Nitroimidazoles) are a kind of artificial synthesized antibacterials.It common are
Metronidazole, Tinidazole, Ornidazole etc..Nitro glyoxaline has unique killing effect to anaerobic bacteria and protozoon, with other antibiotic
It is united and applied in clinical every field.
Metronidazole is developed by pfizer companies of the U.S. in late 1960s and is listed, in the past 50 years, clinical application model
It encloses and increasingly expands, adverse reaction is also increasingly prominent；Tinidazole is equally developed by pfizer companies of the U.S., is listed in 1972,
For treating various anaerobic infections, also can be used as the alternative medicine of metronidazole for caused by helicobacter pylori antral gastritis and
The treatment of peptic ulcer；Ornidazole is succeeded in developing by U.S. Hoffer.M etc. earliest, in May in 1969 25 U.S. Huo it is special
Profit.Hoffmann-LaRocheandCo (Switzerland) company is then transferred, Roche Holding Ag is in~nineteen eighty-three in 1977 successively in moral
The states such as state, France, Italy, Switzerland, Australia, Sweden are listed with trade name " Tiberal ", are after metronidazole, Tinidazole
The novel nitro imidazole derivatives of the third generation later have good anaerobe resistant and anti-trichomonal effect.The active compound of Ornidazole
It is active with intermediate metabolites, act on anaerobic bacteria, amoeba worm, giardia lamblia and trichmonad cell DNA, make its spiral knot
Structure is broken or blocks its transcription to replicate and lethal die.
Laevo-ornidazole is the levo form of Ornidazole, has the function of strength anaerobe resistant and antigen insect infection, for controlling
Treat the prevention of multi-infection disease and operation consent infection caused by sensitive anaerobic bacteria.Clinical application this class medicine primary treatment
Postpartum pelvic infection, oral cavity caused by acute amoebic dysentery, parenteral amcbiasis, urogenital tract trichomonas infection and anaerobic bacteria
Acute infection and abdominal cavity infection etc..Laevo-ornidazole relative to Ornidazole there is unique clinical advantage to be that l-ornidazole is single
One optical isomer, and d-isomer is the main contributor that Ornidazole generates neurotoxicity.
Phosphoric acid l-ornidazole ester disodium is the pro-drug of laevo-ornidazole, and phospholipase is fast under acting in vivo after administration
Speed is degraded to laevo-ornidazole and then plays drug effect.A kind of laevo-ornidazole phosphoric acid is referred in Chinese patent CN101177433
Disodium pentahydrate and its preparation method and application is added 6~20 times into the container equipped with (s)-ornidazole disodium phosphate
95%~70% ethyl alcohol of amount, stirring are warming up to 40 DEG C~55 DEG C, and insulated and stirred 5~30 minutes filters, filtrate is cooled to while hot
Crystallization 8 hours~24 hours, filtering are placed after room temperature in 5~15 DEG C, obtained solid is washed with cold ethyl alcohol, acetone washing, 30~
45 DEG C of drying to moisture are about 22.77%, obtain (s)-ornidazole disodium phosphate pentahydrate.This method drying temperature is 30-45
DEG C, at such a temperature, impurity content increases substantially.
Invention content
In view of the problems of the existing technology, the present invention provides a kind of industrialization of phosphoric acid l-ornidazole ester disodium hydrate
Production method has yield high, and reaction condition is mild, and purity is high, and appearance is good, is suitable for the advantage of industrialized production.
The preparation method of the phosphoric acid l-ornidazole ester disodium hydrate of the present invention, follows the steps below：
(1) laevo-ornidazole is dissolved in organic solvent, is slowly added to phosphorus oxychloride, controlled at 0-99 DEG C；
(2) after completion of the reaction, water is added, continues to react；
(3) after completion of the reaction, it is concentrated to dryness, is dissolved with organic solvent；
(4) pH to 5.0-6.0 is adjusted with sodium hydroxide solution, is filtered to remove insoluble matter；
(5) pH to 6.5-9.0 is adjusted with sodium hydroxide solution, phosphoric acid l-ornidazole ester disodium hydrate is precipitated；
(6) the phosphoric acid l-ornidazole ester disodium of precipitation is collected, water and organic solvent is used in combination further to be refining to obtain phosphoric acid
L-ornidazole ester disodium hydrate fine work.
Wherein, phosphorus oxychloride addition is 0.9~2.5 times of laevo-ornidazole mole in the step (1).
Organic solvent in the step (1) is ethyl acetate, acetonitrile, acetone, toluene, tetrahydrofuran, dichloromethane,
It is preferred that acetonitrile.
Organic solvent in the step (3) is acetonitrile, acetone, tetrahydrofuran, ethyl alcohol, methanol, preferred alcohol.
Inorganic sodium solution used is in the step (4) and step (5)：Sodium bicarbonate, sodium carbonate, sodium hydroxide are molten
Liquid, preferred mass concentration 10-50% sodium hydroxide solutions, more preferable 30% sodium hydroxide solution.
The preferred 7.0-8.0 of pH ranges in the step (5).
The method collected for phosphoric acid l-ornidazole ester disodium in the step (6) includes filtering or rejection filter；It is used to have
Solvent is：Arbitrary two kinds of mixed solvent, preferably second in acetonitrile, acetone, tetrahydrofuran, ethyl alcohol, methanol or above-mentioned solvent
The mixed solvent of alcohol and acetone.
The beneficial effects of the invention are as follows：The present invention provides a kind of preparation sides of phosphoric acid l-ornidazole ester disodium hydrate
Method is esterified with phosphorus oxychloride in organic solvent using l-ornidazole as raw material, after hydrolysis, with sodium hydroxide solution at sodium salt,
Then through being recrystallized to give phosphoric acid l-ornidazole ester disodium hydrate.Preparation method of the present invention is easy, and high income is suitable for industry
Metaplasia is produced.
Specific implementation mode
Embodiment 1
The preparation method of the phosphoric acid l-ornidazole ester disodium hydrate of the present embodiment, follows the steps below：
(1) 4kg laevo-ornidazoles and 12.4kg acetonitriles, stirring and dissolving, 20 DEG C of drops are added into 50L double-layer glass reaction kettles
Add 2.8kg phosphorus oxychloride；
(2) it is added dropwise, is warming up to 45 DEG C, insulated and stirred reacts 12h, and reaction solution is cooled to 20 DEG C hereinafter, slowly dripping
Add 10kg purified waters, finish, is warming up to 60 DEG C, insulated and stirred reacts 3h；
(3) reaction solution is transferred in 50L rotary evaporators, controls 65 DEG C ± 5 DEG C of temperature, vacuum degree >=0.09Mpa subtracts
Pressure is concentrated into condensation and oozes, and collects concentrate, and in 100L double-layer glass reaction kettles, 57kg absolute ethyl alcohols are added；
(4) 0 DEG C~10 DEG C are cooled to, 30% sodium hydroxide solution is slowly added dropwise to pH=5.4~5.8, there are a large amount of whites
Solid is precipitated.0 DEG C~10 DEG C insulated and stirred 1.5h of temperature are controlled, filtrate is collected in filtering；
(5) filtrate is transferred in 100L double-layer glass reaction kettles, controls 0 DEG C~10 DEG C of temperature, 30% hydrogen-oxygen is slowly added dropwise
Change sodium solution to pH=7.5~8.0, phosphoric acid l-ornidazole ester disodium hydrate is precipitated；
(6) 0 DEG C~10 DEG C of temperature is controlled, insulated and stirred crystallization 4h, rejection filter to basic no liquid flows out, and collects filter cake.
2kg/kg purified waters are added into 30L double-layer glass reaction kettles, open stirring, 1kg/kg crude products are added, stirring is extremely
0.05kg/kg medical charcoal is added in dissolving, stirs 10min~20min, filtering, and filtrate is transferred in 100L glass-lined reactors,
0 DEG C~10 DEG C are cooled to, absolute ethyl alcohol/acetone mixed solution is added with stirring, finishes, controls 0 DEG C~10 DEG C of temperature, heat preservation is stirred
Crystallization 4h is mixed, is filtered, filter cake is transferred in 100L glass-lined reactors, and filter cake washed once with 1.60kg/kg acetone, is filtered extremely
Basic no liquid is dripped, and filter cake is collected.After forced air drying 3h, 4.75kg phosphoric acid l-ornidazole ester disodium hydrates, yield are obtained：
53.1% (in terms of anhydride).
Embodiment 2
The preparation method of the phosphoric acid l-ornidazole ester disodium hydrate of the present embodiment, follows the steps below：
(1) 4kg laevo-ornidazoles and 17.4kg acetone, stirring and dissolving, 0 DEG C of drop are added into 50L double-layer glass reaction kettles
Add 2.8kg phosphorus oxychloride；
(2) it is added dropwise, is warming up to 45 DEG C, insulated and stirred reacts 12h, and reaction solution is cooled to 20 DEG C hereinafter, slowly dripping
Add 10kg purified waters, finish, is warming up to 60 DEG C, insulated and stirred reacts 3h；
(3) reaction solution is transferred in 50L rotary evaporators, controls 65 DEG C ± 5 DEG C of temperature, vacuum degree >=0.09Mpa subtracts
Pressure is concentrated into condensation and oozes, and collects concentrate, and in 100L double-layer glass reaction kettles, 57kg absolute ethyl alcohols are added；
(4) 0 DEG C~10 DEG C are cooled to, 30% sodium hydroxide solution is slowly added dropwise to pH=5.4~5.8, there are a large amount of whites
Solid is precipitated.0 DEG C~10 DEG C insulated and stirred 1.5h of temperature are controlled, filtrate is collected in filtering；
(5) filtrate is transferred in 100L double-layer glass reaction kettles, controls 0 DEG C~10 DEG C of temperature, 30% hydrogen-oxygen is slowly added dropwise
Change sodium solution to pH=7.5~8.0, phosphoric acid l-ornidazole ester disodium hydrate is precipitated；
(6) 0 DEG C~10 DEG C of temperature is controlled, insulated and stirred crystallization 4h, rejection filter to basic no liquid flows out, and collects filter cake.
2kg/kg purified waters are added into 30L double-layer glass reaction kettles, open stirring, 1kg/kg crude products are added, stirring is extremely
0.05kg/kg medical charcoal is added in dissolving, stirs 10min~20min, filtering, and filtrate is transferred in 100L glass-lined reactors,
0 DEG C~10 DEG C are cooled to, absolute ethyl alcohol/acetone mixed solution is added with stirring, finishes, controls 0 DEG C~10 DEG C of temperature, heat preservation is stirred
Crystallization 4h is mixed, is filtered, filter cake is transferred in 100L glass-lined reactors, and filter cake washed once with 1.60kg/kg acetone, is filtered extremely
Basic no liquid is dripped, and filter cake is collected.After forced air drying 3h, 4.69kg phosphoric acid l-ornidazole ester disodium hydrates, yield are obtained：
52.8% (in terms of anhydride).
Embodiment 3
The preparation method of the phosphoric acid l-ornidazole ester disodium hydrate of the present embodiment, follows the steps below：
(1) addition 4kg laevo-ornidazoles and 21.6kg tetrahydrofurans into 50L double-layer glass reaction kettles, stirring and dissolving, 99
DEG C be added dropwise 2.8kg phosphorus oxychloride；
(2) it is added dropwise, is warming up to 45 DEG C, insulated and stirred reacts 12h, and reaction solution is cooled to 20 DEG C hereinafter, slowly dripping
Add 10kg purified waters, finish, is warming up to 60 DEG C, insulated and stirred reacts 3h；
(3) reaction solution is transferred in 50L rotary evaporators, controls 65 DEG C ± 5 DEG C of temperature, vacuum degree >=0.09Mpa subtracts
Pressure is concentrated into condensation and oozes, and collects concentrate, and in 100L double-layer glass reaction kettles, 57kg absolute ethyl alcohols are added；
(4) 0 DEG C~10 DEG C are cooled to, 30% sodium hydroxide solution is slowly added dropwise to pH=5.4~5.8, there are a large amount of whites
Solid is precipitated.0 DEG C~10 DEG C insulated and stirred 1.5h of temperature are controlled, filtrate is collected in filtering；
(5) filtrate is transferred in 100L double-layer glass reaction kettles, controls 0 DEG C~10 DEG C of temperature, 30% hydrogen-oxygen is slowly added dropwise
Change sodium solution to pH=7.0~8.0, phosphoric acid l-ornidazole ester disodium hydrate is precipitated；
(6) 0 DEG C~10 DEG C of temperature is controlled, insulated and stirred crystallization 4h, rejection filter to basic no liquid flows out, and collects filter cake.
2kg/kg purified waters are added into 30L double-layer glass reaction kettles, open stirring, 1kg/kg crude products are added, stirring is extremely
0.05kg/kg medical charcoal is added in dissolving, stirs 10min~20min, filtering, and filtrate is transferred in 100L glass-lined reactors,
0 DEG C~10 DEG C are cooled to, absolute ethyl alcohol/acetone mixed solution is added with stirring, finishes, controls 0 DEG C~10 DEG C of temperature, heat preservation is stirred
Crystallization 4h is mixed, is filtered, filter cake is transferred in 100L glass-lined reactors, and filter cake washed once with 1.60kg/kg acetone, is filtered extremely
Basic no liquid is dripped, and filter cake is collected.After forced air drying 3h, 4.55kg phosphoric acid l-ornidazole ester disodium hydrates, yield are obtained：
52.1% (in terms of anhydride).
Claims (7)
1. a kind of preparation method of phosphoric acid l-ornidazole ester disodium hydrate, it is characterised in that follow the steps below：
(1) laevo-ornidazole is dissolved in organic solvent, is slowly added to phosphorus oxychloride, controlled at 0-99 DEG C；
(2) after completion of the reaction, water is added, continues to react；
(3) after completion of the reaction, it is concentrated to dryness, is dissolved with organic solvent；
(4) pH to 5.0-6.0 is adjusted with sodium hydroxide solution, is filtered to remove insoluble matter；
(5) pH to 6.5-9.0 is adjusted with sodium hydroxide solution, phosphoric acid l-ornidazole ester disodium hydrate is precipitated；
(6) the phosphoric acid l-ornidazole ester disodium of precipitation is collected, water and organic solvent is used in combination further to be refining to obtain the left Austria of phosphoric acid
Nitre azoles ester disodium hydrate fine work.
2. a kind of preparation method of phosphoric acid l-ornidazole ester disodium hydrate according to claim 1, it is characterised in that institute
Phosphorus oxychloride addition is 0.9~2.5 times of laevo-ornidazole mole in the step of stating (1).
3. a kind of preparation method of phosphoric acid l-ornidazole ester disodium hydrate according to claim 1, it is characterised in that institute
Organic solvent in the step of stating (1) is ethyl acetate, acetonitrile, acetone, toluene, tetrahydrofuran, dichloromethane, preferably acetonitrile.
4. a kind of preparation method of phosphoric acid l-ornidazole ester disodium hydrate according to claim 1, it is characterised in that institute
Organic solvent in the step of stating (3) is acetonitrile, acetone, tetrahydrofuran, ethyl alcohol, methanol, preferred alcohol.
5. a kind of preparation method of phosphoric acid l-ornidazole ester disodium hydrate according to claim 1, it is characterised in that institute
Inorganic sodium solution used is in the step of stating (4) and step (5)：Sodium bicarbonate, sodium carbonate, sodium hydroxide solution, preferably matter
Measure concentration 10-50% sodium hydroxide solutions, more preferable 30% sodium hydroxide solution.
6. a kind of preparation method of phosphoric acid l-ornidazole ester disodium hydrate according to claim 1, it is characterised in that institute
The preferred 7.0-8.0 of pH ranges in the step of stating (5).
7. a kind of preparation method of phosphoric acid l-ornidazole ester disodium hydrate according to claim 1, it is characterised in that institute
The method collected for phosphoric acid l-ornidazole ester disodium in the step of stating (6) includes filtering or rejection filter；Organic solvent used is：Second
Arbitrary two kinds of mixed solvent in nitrile, acetone, tetrahydrofuran, ethyl alcohol, methanol or above-mentioned solvent, preferred alcohol and acetone mix
Bonding solvent.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109748934A (en) * | 2019-02-14 | 2019-05-14 | 扬子江药业集团南京海陵药业有限公司 | A kind of phosphoric acid l-ornidazole ester disodium heptahydrate crystal form and preparation method thereof |
| CN114075242A (en) * | 2020-08-12 | 2022-02-22 | 扬子江药业集团南京海陵药业有限公司 | Industrial production method of levoornidazole disodium phosphate |
| CN114478391A (en) * | 2020-10-26 | 2022-05-13 | 南京锐志生物医药有限公司 | Ornidazole ester prodrug, pharmaceutical composition, preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109748934A (en) * | 2019-02-14 | 2019-05-14 | 扬子江药业集团南京海陵药业有限公司 | A kind of phosphoric acid l-ornidazole ester disodium heptahydrate crystal form and preparation method thereof |
| CN109748934B (en) * | 2019-02-14 | 2021-05-11 | 扬子江药业集团南京海陵药业有限公司 | Levoornidazole disodium phosphate heptahydrate crystal form and preparation method thereof |
| CN114075242A (en) * | 2020-08-12 | 2022-02-22 | 扬子江药业集团南京海陵药业有限公司 | Industrial production method of levoornidazole disodium phosphate |
| CN114075242B (en) * | 2020-08-12 | 2024-02-06 | 扬子江药业集团南京海陵药业有限公司 | Industrial production method of disodium salt of left ornidazole phosphate |
| CN114478391A (en) * | 2020-10-26 | 2022-05-13 | 南京锐志生物医药有限公司 | Ornidazole ester prodrug, pharmaceutical composition, preparation method and application thereof |
| CN114478391B (en) * | 2020-10-26 | 2023-09-15 | 南京锐志生物医药有限公司 | Ornidazole ester prodrug, pharmaceutical composition, and preparation method and application thereof |
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Application publication date: 20180817 |