CN103553942B - A kind of preparation method of phenylephrine hydrochloride impurity - Google Patents
A kind of preparation method of phenylephrine hydrochloride impurity Download PDFInfo
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- CN103553942B CN103553942B CN201310570967.9A CN201310570967A CN103553942B CN 103553942 B CN103553942 B CN 103553942B CN 201310570967 A CN201310570967 A CN 201310570967A CN 103553942 B CN103553942 B CN 103553942B
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Abstract
The invention belongs to medicinal chemistry art, the invention discloses a kind of phenylephrine hydrochloride impurity D, be i.e. 2-(N-benzylmethylamine base)-1-(3-hydroxy phenyl) ethanol, and preparation method thereof; Impurity D is one of major impurity of Phenylephrine Hydrochloride bulk drug; By the synthesis to phenylephrine hydrochloride impurity D, for phenylephrine hydrochloride impurity inspection, quantitatively and qualitative analysis provide reference substance, thus improve the adrenergic quality standard of hydrochloric acid deoxidation kidney, for Phenylephrine Hydrochloride safe medication provides guidance, the hydrochloric acid deoxidation kidney suprarenin simultaneously for obtaining meeting EP quality standard provides and effectively detects foundation; Fig. 1 is impurity D proton nmr spectra spectrogram.
Description
Technical field
The invention belongs to medicinal chemistry art, the invention discloses a kind of phenylephrine hydrochloride impurity D, be i.e. 2-(N-benzylmethylamine base)-1-(3-hydroxy phenyl) ethanol, and preparation method thereof.
Background technology
Phenylephrine Hydrochloride is alpha adrenergic receptor excitomotor, directly acts on the sympathomimetic amine medicine of acceptor, but sometimes also comes into force from the release of storage position indirectly by promotion synephrine.Act on α acceptor places such as (especially) skin, mucous membrane, internal organ, cause vasoconstriction, Peripheral resistance increases, and systolic pressure and diastolic pressure are all raised.There is obvious vasoconstrictor effects.Its effect is similar to synephrine, but more weak and lasting, and toxicity is less.Can reflectivity ground excited vagus, make decreased heart rate, and have of short duration expansion pupil effect.Clinical being generally used for infects toxic and anaphylactic shock, supraventricular tachycardia.Phenylephrine Hydrochloride has good security and reliable curative effect, is applied to clinical just more and more widely.
The chemistry of impurity D is called: 2-(N-benzylmethylamine base)-1-(3-hydroxy phenyl) ethanol, structure is as follows:
Carrying out finding in the detection of Phenylephrine Hydrochloride drug quality, impurity D is present in Phenylephrine Hydrochloride and preparation thereof as impurity.
Through the impurity that structural confirmation and mass analysis checking impurity D are side reaction generation in Phenylephrine Hydrochloride building-up process.
Carrying out in drug quality testing process, needing highly purified impurity and be used as reference substance, for controlling the quality that may contain the medicine of this impurity.Therefore, highly purified known impurities compound must be synthesized.Impurity D and synthetic method thereof, have no report.
Therefore, the present invention mainly solves the associated problem that in Phenylephrine Hydrochloride medicine, impurity D synthesizes.
Summary of the invention
We are in the quality examination process of carrying out Phenylephrine Hydrochloride bulk drug and preparation, find that determine through carefully studying, surprised this impurity of discovery is compound shown in formula I containing 1 impurity in Phenylephrine Hydrochloride raw material.
The invention provides the synthetic method of phenylephrine hydrochloride impurity D.Impurity D can be obtained with reduction reagent react by benzyl deoxidation Adrenalone or benzyl deoxidation Adrenalone salt, and synthetic route is as follows:
The preparation method of phenylephrine hydrochloride impurity D is:
(1) be dissolved in solvent by benzyl deoxidation Adrenalone or its salt, stir, add and go back original reagent, react, Liquid Detection impurity D peak area percent is not less than 80%
(2) concentrating under reduced pressure removes solvent, adds water, and add alkali reagent and regulate pH to 9-11, add organic solvent and extract, concentrating under reduced pressure organic solvent, to dry, obtain impurity D purity and is not less than 90%
(3) by gained crude product impurity D in organic solvent recrystallization obtain impurity D, purity more than 99%.
Above-mentioned its salt of benzyl deoxidation Adrenalone is hydrochloride, vitriol etc.;
Above-mentioned solvent be tetrahydrofuran (THF), ethyl acetate, propyl acetate, butylacetate, water or tetrahydrofuran (THF), water mix reagent;
The alkali reagent of above-mentioned adjustment pH be triethylamine, sodium hydroxide, sodium carbonate, sodium bicarbonate, ammoniacal liquor etc.;
Said extracted organic solvent is methylene dichloride, trichloromethane, ethyl acetate, propyl acetate, butylacetate etc.;
Above-mentioned original reagent of going back is iron powder, zinc powder, sodium borohydride, lithium aluminum hydride, aluminum isopropylate, tetra-n-butyl tetrahydrochysene ammonium borate, red aluminium etc.
Purification process can simple recrystallization, also can use column chromatography, or adopt liquid phase separation preparation.Recrystallization solvent can use methyl alcohol, ethanol, propyl alcohol, methyl acetate, ethyl acetate, propyl acetate, butylacetate or methyl alcohol, ethanol, propyl alcohol, methyl acetate, ethyl acetate, propyl acetate, n-butyl acetate mixed solvent etc.Also can adopt column chromatography or liquid phase separation preparation, its moving phase is methanol-water or acetonitrile water or degree or the gradient elution such as methyl alcohol, acetonitrile water, accepts product flow point, is concentrated into dry product.We show in research, can obtain purity more than 99% product, can be used to do quality approach completely.Can be used for the contamination levels product in Control of drug quality or impurity reference substance.
We show in research, and in Phenylephrine Hydrochloride bulk drug, impurity HPLC peak position is consistent with our synthetic compound I liquid phase retention time, and liquid matter molecular weight is consistent, and its Compound I nuclear magnetic data ownership rationally.Therefore illustrate that synthetic compound I is the impurity in Phenylephrine Hydrochloride bulk drug, determine through LC-MS, both molecular weight are consistent.
Impurity D hydrogen nuclear magnetic resonance modal data:
1hNMR(CDCl
3): δ 2.24 (3H ,-NCH
3), 2.36-2.53 (2H ,-CH2-), 3.36-3.44 (2H ,-CH2-), 4.60 (1H ,-CH-), 6.38 (2H ,-OH), 6.69-7.05 (4H phenyl ring) 7.725 (5H, phenyl ring).
Accompanying drawing explanation
Accompanying drawing 1 impurity D proton nmr spectra spectrogram
Embodiment
Embodiment 1: the preparation method 1 of impurity D
In 1L reaction flask, add water 300mL and benzyl deoxidation Adrenalone hydrochloride 30g, be stirred to dissolving, under stirring, slowly add sodium borohydride 10g, there is gas to produce, after sodium borohydride adds, stir under room temperature (20-30 DEG C), Liquid Detection, impurity D peak area percent 92%.After completion of the reaction, add ammoniacal liquor adjust pH to 9-10, then add methylene dichloride 200mL, stir 15 minutes, leave standstill 15 minutes, carry out layering, upper strata is aqueous phase, and lower floor is organic phase, and organic phase retains, aqueous phase uses dichloromethane extraction 2 times again, uses methylene dichloride 100mL at every turn, merges organic phase, be evaporated to dripless, obtain impurity D crude product, color brown oily matter, purity 96%.Impurity D is obtained, about 16.6g, yield 62.9%, purity 99.5% with recrystallization in 15m ethanol and 30ml butylacetate
Embodiment 2: the preparation method 2 of impurity D
In 10ml reaction flask, add tetrahydrofuran (THF) 3mL and benzyl deoxidation Adrenalone 0.5g, stirring, is white suspension, slowly add lithium aluminum hydride 0.5g under stirring, after adding, stir under room temperature (20-30 DEG C), Liquid Detection, impurity D peak area percent 82%.After completion of the reaction, filter, filtrate be concentrated into dry, then add methylene dichloride 10mL and water 10ml, carry out layering, organic phase retains, and is evaporated to dripless, obtains impurity D crude product, color brown oily matter, purity 84%.Impurity D is obtained, about 0.26g, yield 52%, purity 93.5% with recrystallization in 2ml ethyl acetate
Embodiment 3: different recrystallization solvents prepares yield to impurity D's, quality impact:
According to the preparation method 1 of impurity D, select recrystallization reagent to be respectively: the mixed solvent of ethanol, ethyl acetate, butylacetate, ethanol and butylacetate, complete 4 experiments, obtain 4 samples, its yield, qualitative data sees the following form:
Conclusion: recrystallization reagent adopts ethanol and butylacetate mix reagent, and yield, quality are relatively best.
Claims (1)
1. a preparation method of phenylephrine hydrochloride impurity D, described impurity D is as shown in the formula shown in I:
Its preparation method comprises the steps:
(1) be dissolved in 300ml water by 30g benzyl deoxidation Adrenalone hydrochloride, stir, add 10g sodium borohydride, react, impurity D peak area percent is 92-93%;
(2) add ammoniacal liquor adjust ph to 9-10, add 200ml methylene dichloride and extract, be concentrated into dry impurity D crude product, purity 96-97%;
(3) impurity D crude product recrystallization in 15m ethanol and 30ml butylacetate is obtained impurity D.
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| CN113717068A (en) * | 2021-09-28 | 2021-11-30 | 广州佳途科技股份有限公司 | Phenyladrenaline impurity and preparation method and application thereof |
| CN115950992B (en) * | 2023-03-15 | 2023-06-09 | 苏州朗易生物医药研究有限公司 | Detection method for related substances in phenylephrine ketorolac solution and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6187956B1 (en) * | 1999-01-21 | 2001-02-13 | Boehringer Ingelheim Pharma Kg | Method for preparing of L-phenylephrine hydrochloride |
| CN101921197A (en) * | 2010-08-18 | 2010-12-22 | 潍坊幸福药业有限公司 | Preparation method of phenylephrine |
| CN102381990A (en) * | 2010-08-31 | 2012-03-21 | 凯瑞斯德生化(苏州)有限公司 | Preparation method of optically active N-benzyl phenylephrine |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6187956B1 (en) * | 1999-01-21 | 2001-02-13 | Boehringer Ingelheim Pharma Kg | Method for preparing of L-phenylephrine hydrochloride |
| CN101921197A (en) * | 2010-08-18 | 2010-12-22 | 潍坊幸福药业有限公司 | Preparation method of phenylephrine |
| CN102381990A (en) * | 2010-08-31 | 2012-03-21 | 凯瑞斯德生化(苏州)有限公司 | Preparation method of optically active N-benzyl phenylephrine |
Non-Patent Citations (1)
| Title |
|---|
| 拟肾上腺素药盐酸甲氧明的绿色合成;谢宇等;《有机化学》;20101231;第30卷(第2期);第282-284页 * |
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