CN118026877A - Preparation method of metoclopramide EP impurity F - Google Patents
Preparation method of metoclopramide EP impurity F Download PDFInfo
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- CN118026877A CN118026877A CN202410182488.8A CN202410182488A CN118026877A CN 118026877 A CN118026877 A CN 118026877A CN 202410182488 A CN202410182488 A CN 202410182488A CN 118026877 A CN118026877 A CN 118026877A
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- metoclopramide
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- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 229960004503 metoclopramide Drugs 0.000 title claims abstract description 50
- 239000012535 impurity Substances 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 7
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229950003442 methoprene Drugs 0.000 claims abstract description 6
- 229930002897 methoprene Natural products 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 238000002156 mixing Methods 0.000 claims abstract description 5
- 238000000746 purification Methods 0.000 claims abstract description 5
- 230000001335 demethylating effect Effects 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 6
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 5
- BJDYCCHRZIFCGN-UHFFFAOYSA-N pyridin-1-ium;iodide Chemical compound I.C1=CC=NC=C1 BJDYCCHRZIFCGN-UHFFFAOYSA-N 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000012649 demethylating agent Substances 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 238000004537 pulping Methods 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 239000005457 ice water Substances 0.000 description 4
- 238000010606 normalization Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010028813 Nausea Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000008693 nausea Effects 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000000706 effect on dopamine Effects 0.000 description 1
- QPUSANCBJDDXSA-UHFFFAOYSA-N ethanethiol;sodium Chemical compound [Na].CCS QPUSANCBJDDXSA-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
- 239000004083 gastrointestinal agent Substances 0.000 description 1
- 229940127227 gastrointestinal drug Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of metoclopramide EP impurity F, which comprises the following steps: mixing and reacting methoprene serving as a raw material in a solvent and a demethylating reagent; and then separating and purifying to obtain the metoclopramide EP impurity F. The preparation method of the metoclopramide EP impurity F has mild conditions at 0-100 ℃, the reagent is friendly to the external environment, the metoclopramide EP impurity F is directly prepared in one step, the production efficiency is high, the raw materials are cheap and easy to obtain, the post-treatment purification is simple, the yield is high, and the purity meets the requirements.
Description
Technical Field
The invention relates to the technical field of metoclopramide EP impurity F, in particular to a preparation method of metoclopramide EP impurity F.
Background
Metoclopramide can be used to treat nausea, help relieve gastric reflux, or improve gastric emptying. Metoclopramide increases motility of the upper digestive tract, allows faster transport of food through the gastrointestinal tract, and reduces symptoms such as nausea. However, it has not been determined how methoprene exerts this effect, and is believed to be derived from its effect on dopamine receptors in the brain and intestinal tract. Metoclopramide is an antiemetic drug and may also be referred to as a pro-gastrointestinal drug.
The chemical name of the metoclopramide is 4-amino-5-chloro-N- (2- (diethylamino) ethyl) -2-methoxybenzamide, and the structural formula is shown as follows:
in the synthesis process of the metoclopramide, the methoxy group on the benzene ring can be subjected to demethylation under the acidic condition, so that the metoclopramide EP impurity F with phenolic hydroxyl is generated.
The quality control requirements (such as consistency evaluation and the like) on the imitation pharmacy in the domestic market are high at present, and one important standard for improving the quality of the medicines is to improve the purity of the medicines. According to the requirements of the European pharmacopoeia on the types and the contents of the metoclopramide impurities, the invention designs and synthesizes one of the metoclopramide related impurities, namely the metoclopramide EP impurity F, and can obtain an impurity reference substance for quality detection so as to control the quality of the metoclopramide and ensure the curative effect of the metoclopramide.
The chemical structure of metoclopramide EP impurity F is mentioned in Page 3254-3255, european Pharmacopoeia, 10.0. EP431561A2 reports a preparation process in which metoclopramide is reacted with pyridine hydrochloride at a high temperature of 185-190℃for 2h. The method reported in US4820715A is to react metoclopramide with in-situ generated sodium ethanethiol to remove methyl and generate a target product. The method reported in the patent is strict in condition, and the method uses reagents with high temperature and great odor, so that the method is extremely harmful to the environment and experimental staff.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention provides a preparation method of metoclopramide EP impurity F,
In order to achieve the above purpose, the invention provides a preparation method of metoclopramide EP impurity F, comprising the following steps:
Step S1: mixing and reacting methoprene serving as a raw material in a solvent and a demethylating reagent;
Step S2: then separating and purifying to obtain the metoclopramide EP impurity F, wherein the reaction equation is as follows:
preferably, the solvent in the step S1 is selected from one or more of water, acetonitrile, N-dimethylformamide, tetrahydrofuran or 1, 4-dioxane.
Preferably, the demethylating agent in step S1 is selected from one or more of AlCl 3, 48% aqueous hydrobromic acid, BBr 3、Me3 SiI, pyridinium hydroiodic acid salt, naSEt, liCl.
Preferably, the demethylating agent in step S1 is selected from the group consisting of AlCl 3、% aqueous hydrobromic acid, BBr 3、Me3 SiI and pyridinium hydroiodic acid.
Preferably, the reaction temperature of the mixing reaction in the step S1 is 0-100 ℃ and the reaction time is 1-48h.
Preferably, the specific steps of separation and purification in the step S2 are: and cooling the reaction liquid to room temperature, regulating the PH until solid is separated out, pulping and filtering by using ethyl acetate, and then drying in vacuum to obtain the metoclopramide EP impurity F product.
The technical scheme of the invention has the following beneficial effects: the preparation method of the metoclopramide EP impurity F has mild conditions at 0-100 ℃, the reagent is friendly to the external environment, the metoclopramide EP impurity F is directly prepared in one step, the production efficiency is high, the raw materials are cheap and easy to obtain, the post-treatment purification is simple, the yield is high, the purity is up to 60-90%, and the purity is over 95%, so that the method meets the requirements.
Drawings
FIG. 1 is a mass spectrum of the inventive metoclopramide EP impurity F;
FIG. 2 is a nuclear magnetic resonance diagram of the inventive metoclopramide EP impurity F;
FIG. 3 is an HPLC chart of the inventive metoclopramide EP impurity F.
Detailed Description
The invention will be further described with reference to the drawings and the specific examples.
Example 1
Referring to fig. 1 to 3, the present invention provides a method for preparing metoclopramide EP impurity F:
Metoclopramide (2 g,6.7 mmol) was dissolved in acetonitrile (25 mL) and anhydrous AlCl 3 (5 g,37.5 mmol) was added at room temperature; heating to 60 ℃ in an oil bath, reacting for 6 hours, cooling to room temperature, slowly adding ice water (I00 mL), dropwise adding 25% ammonia water until the pH is 5-6, precipitating solid, filtering, pulping a filter cake with ethyl acetate, then drying in vacuum to obtain 1.3 g of a product, and finally calculating to obtain the metoclopramide EP impurity F with the yield of 68.4% and the purity of 99.1% detected by liquid chromatography (see figure 3). The spectra are shown in FIGS. 1 and 2 below, with ESI-LCMS (m/z): 286.02 (M+H) + Nuclear magnetism HNMR in DMSO,δ12.44(s,1H),8.79(s,1H),7.80(s,1H),6.23(s,1H),5.83(s,2H),3.63～3.59(m,2H),3.21-3.17(m,6H),1.24～1.20(t,6H).
Example 2
Methoprene (2 g,6.7 mmol) is added into 48% hydrobromic acid aqueous solution (25 mL), heated and refluxed for 4h in an oil bath, cooled to room temperature, saturated sodium bicarbonate is added dropwise until the pH is 5-6, the white solid is separated out, stirred for 30min, filtered, the filter cake is rinsed with ice water, the filter cake is pulped with ethyl acetate, the white solid is obtained by vacuum drying, 1.2 g is obtained, and finally the yield 63% of the methoprene EP impurity F is obtained by calculation through an HPLC area normalization method, and the purity is 95.2%. The spectrum is the same as in example 1.
Example 3:
Metoclopramide (2 g,6.7 mmol) was dissolved in acetonitrile (25 mL), cooled to 0deg.C, and BBr 3 (20.1 mL,1 mol/L) was added dropwise. The reaction was then allowed to slowly warm to room temperature and stirred overnight. And cooling the reaction system to-78 ℃, and adding methanol for quenching. The white solid is separated out, stirred for 30min, filtered, the filter cake is rinsed with ice water, the filter cake is pulped with ethyl acetate, 1.67 g of white solid is obtained by vacuum drying, and finally the yield of the metoclopramide EP impurity F is 87.9% and the purity is 97.2% through calculation by an HPLC area normalization method. The spectrum is the same as in example 1.
Example 4:
Metoclopramide (2 g,6.7 mmol) was dissolved in chloroform (25 mL) and Me 3 SiI (1.75 g) was added dropwise. The reaction was then stirred at room temperature overnight. And cooling the reaction system to 0 ℃, and adding methanol for quenching. After quenching, the mixture was poured into methanol (25 mL) and stirred for 30min. The solvent was removed by spin-drying under reduced pressure, the residue was slurried with ethyl acetate and dried in vacuo to give 1.55 g of a white solid, and finally the yield of metoclopramide EP impurity F was calculated by HPLC area normalization to give 81.6% with a purity of 96.9%. The spectrum is the same as in example 1.
Example 5:
metoclopramide (2 g,6.7 mmol) was dissolved in acetonitrile (25 mL) and pyridinium hydroiodide (2.08 g) was added. The reaction was then stirred at reflux overnight. Then cooling the reaction system to 0 ℃, dropwise adding saturated sodium bicarbonate until the pH is 5-6, precipitating white solid, and stirring for 30min. Filtering, rinsing the filter cake with ice water, pulping the filter cake with ethyl acetate, vacuum drying to obtain 1.47 g of white solid, and finally calculating by an HPLC area normalization method to obtain the yield 77.4% and the purity 98.7% of metoclopramide EP impurity F. The spectrum is the same as in example 1.
As can be seen from examples 1-5, the preparation method of the metoclopramide EP impurity F has the advantages of mild reaction conditions at 0-100 ℃, environment-friendly reagent selection, high production efficiency, cheap and easily available raw materials, simple post-treatment and purification, high yield up to 60-90%, purity over 95% and accordance with requirements, and can be used for directly preparing the metoclopramide EP impurity F in one step.
The foregoing description is only of the preferred embodiments of the present invention and is not intended to limit the scope of the invention, and all equivalent structural changes made by the description of the present invention and the accompanying drawings or direct/indirect application in other related technical fields are included in the scope of the invention.
Claims (6)
1. The preparation method of the metoclopramide EP impurity F is characterized by comprising the following steps:
Step S1: mixing and reacting methoprene serving as a raw material in a solvent and a demethylating reagent;
Step S2: then separating and purifying to obtain the metoclopramide EP impurity F, wherein the reaction equation is as follows:
2. the method for preparing metoclopramide EP impurity F according to claim 1, wherein the solvent in step S1 is one or more selected from water, acetonitrile, N-dimethylformamide, tetrahydrofuran and 1, 4-dioxane.
3. The method for preparing the metoclopramide EP impurity F according to claim 1, wherein the demethylating agent in step S1 is one or more selected from AlCl 3, 48% aqueous hydrobromic acid, BBr 3、Me3 SiI, pyridinium hydroiodic acid, naSEt, liCl.
4. A process for the preparation of metoclopramide EP impurity F according to claim 3, characterized in that the demethylating agent in step S1 is selected from the group consisting of AlCl 3、% aqueous hydrobromic acid, BBr 3、Me3 SiI and pyridinium hydroiodic acid.
5. The method for preparing metoclopramide EP impurity F according to claim 1, wherein the reaction temperature of the mixing reaction in step S1 is 0 to 100 ℃ and the reaction time is 1 to 48 hours.
6. The method for preparing metoclopramide EP impurity F according to claim 1, characterized in that the specific steps of separation and purification in step S2 are: and cooling the reaction liquid to room temperature, regulating the PH until solid is separated out, pulping and filtering by using ethyl acetate, and then drying in vacuum to obtain the metoclopramide EP impurity F product.
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| CN202410182488.8A CN118026877A (en) | 2024-02-19 | 2024-02-19 | Preparation method of metoclopramide EP impurity F |
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| CN202410182488.8A CN118026877A (en) | 2024-02-19 | 2024-02-19 | Preparation method of metoclopramide EP impurity F |
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