CN106083699A - A kind of preparation method of doxylamine impurity G - Google Patents
A kind of preparation method of doxylamine impurity G Download PDFInfo
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D213/30—Oxygen atoms
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Abstract
The invention discloses the preparation method of a kind of doxylamine impurity G, comprise the steps: that doxylamine and phenyl chloroformate reaction obtain intermediate product；Intermediate product hydrolysis obtains doxylamine impurity G.The preparation method of the doxylamine impurity G that the present invention proposes, is reacted with phenyl chloroformate by doxylamine, is sloughed by the methyl in atom N and obtain doxylamine impurity G, and synthetic route is short, reaction selectivity is high, and raw material is easy to get, and product purity is high, reaction condition is gentle, economic and environment-friendly, easy and simple to handle.
Description
Technical field
The present invention relates to pharmaceutical chemistry technical field, particularly relate to the preparation method of a kind of doxylamine impurity G.
Background technology
Doxylamine succinate (doxylamine succinate), chemical name: N, N-dimethyl-2-[1-phenyl-1-
(2-pyridine) ethyoxyl] ethamine succinate, CAS:562-10-7.Doxylamine succinate is a class ethanolamines medicine, tool
There are antihistamine effect, cholinolytic effect and significant sedation, feature that its activity is strong and gastrointestinal side effect is low etc., it is adaptable to
Multiple anaphylaxis dermatosis, pollinosis, allergic rhinitis, asthmatic bronchitis etc..In October, 1978, FDA ratified CHATTEM
The doxylamine 25mg tablet listing of company, is adapted to assist in and alleviates difficulty falling asleep, within 1979, become OTC, in JIUYUE, 1996 approval and
Ratify the imitation medicine listing of LNK company in August, 2004.On April 8th, 2013 FDA approval Diclegis (doxylamine succinate and
Pyridoxine hydrochloride) it is oral sustained release sheet, for treatment, the best gravid woman is reacted in conservative process and stand nausea and vomiting.Its
Structural formula is as follows:
The key of doxylamine succinate synthesis essentially consists in the control of impurity, the therefore conjunction of doxylamine succinate impurity
Become research tool to be of great significance, may be used for the impurity quantification during doxylamine succinate produces and quantitative analysis, from
And the quality standard of doxylamine succinate can be improved.The impurity bag that doxylamine succinate research needs pointed out by existing document
Include:
1, doxylamine impurity A, chemical name: N, N-dimethyl-2-[1-phenyl-1-(4-pyridine) ethyoxyl] ethamine, knot
Structure formula is as follows:
2, doxylamine impurity B, chemical name: 2-pyridinylphenyl carbinol methine, structural formula is as follows:
3, doxylamine impurity C, chemical name: N, N-dimethyl-2-[1-phenyl-1-(4-pyridine) methoxyl group] ethamine, knot
Structure formula is as follows:
4, doxylamine impurity D, chemical name: 2-benzoyl pyridine, structural formula is as follows:
5, doxylamine impurity G, chemical name: N-methyl-2-[1-phenyl-1-(2-pyridine) ethyoxyl] ethamine, structural formula
As follows:
Synthesis document for doxylamine impurity reports that document is little, especially to doxylamine impurity the most both at home and abroad
The synthesis of G has not yet to see document report.
" technological guidance's principle of chemicals impurity research " ([H] GPII3-l, page 6～7) points out: organic impurities
The general many employing HPLC methods of detection.As used HPLC method, must use peak area method, concrete quantitative approach uses external standard method (impurity
Standard reference), quantified by external standard method is more accurate.
Doxylamine impurity G is the impurity must paid close attention in doxylamine quality standard, and it is miscellaneous for doxylamine
The correlational study meaning of matter is the most great.Therefore it provides a kind of simple and effective side preparing highly purified doxylamine impurity G
Method, the correlational study for doxylamine impurity is significant.It may be used for the impurity quantification during doxylamine produces and determines
Quantitative analysis, such that it is able to improve the quality standard of doxylamine, provides important directive significance for people's safe medication.
Summary of the invention
The technical problem existed based on background technology, the present invention proposes the preparation method of a kind of doxylamine impurity G, logical
Crossing doxylamine to react with phenyl chloroformate, sloughed by the methyl in atom N and obtain doxylamine impurity G, method is easy, reaction
Mild condition, raw material is easy to get, and pollutant are few, and purity is high, economic and environment-friendly.
The preparation method of a kind of doxylamine impurity G that the present invention proposes, comprises the steps:
S1, doxylamine (I) and phenyl chloroformate reaction obtain intermediate product (II)；
The hydrolysis of S2, intermediate product (II) obtains doxylamine impurity G (III)；
Above-mentioned synthesis flow is as follows:
Preferably, in S1, doxylamine (I) react with phenyl chloroformate in the basic conditions, obtains centre after column chromatography
Product (II).
Preferably, in S1, doxylamine (I) is added mix homogeneously in the first solvent, is subsequently added into the first highly basic, then puts
In ice bath, drip phenyl chloroformate, heat up after dropping, insulation, washing, it is dried, after column chromatography, obtains intermediate product
(Ⅱ)。
Preferably, in S1, doxylamine is 1:1～1.5, preferably 1:1.1 with the mol ratio of phenyl chloroformate.
Preferably, in S1, the mass volume ratio (g/mL) of doxylamine and the first solvent is 1:5～10, preferably 1:6.
Preferably, in S1, the first solvent is in toluene, dimethylbenzene, dimethyl sulfoxide, n-butyl alcohol, DMF
One or more compositionss, preferably toluene.
Preferably, in S1, the mol ratio of doxylamine and the first highly basic is 1:2～4, preferably 1:3.
Preferably, in S1, the first highly basic is one or more combinations in sodium hydroxide, potassium hydroxide, triethylamine
Thing, preferably triethylamine.
Preferably, in S1, after dropping, it is warming up to 48～52 DEG C, is incubated 4.5～5.5h.
Preferably, in S1, in column chromatography procedure, eluant uses petrol ether/ethyl acetate system.
Preferably, petroleum ether: the volume ratio of ethyl acetate is 6～10:1, preferably 8:1.
Preferably, in S2, intermediate product (II) hydrolyzes in the basic conditions and obtains doxylamine impurity G (III).
Preferably, in S2, intermediate product (II) is added mix homogeneously in the second solvent, be subsequently added into the second highly basic, rise
Temperature is to backflow, insulation backflow, then lowers the temperature, sucking filtration, and washing is dried to obtain doxylamine impurity G (III).
Preferably, in S2, insulation return time is 2～2.5h.
Preferably, in S2, it is cooled to 4～6 DEG C.
Preferably, in S2, intermediate product (II) is 1:5～15, preferably 1:10 with the mol ratio of the second highly basic.
Preferably, in S2, the second highly basic is one or more combinations in sodium hydroxide, potassium hydroxide, triethylamine
Thing, preferably potassium hydroxide.
Preferably, in S2, intermediate product (II) is 1:5～15 with the mass volume ratio (g/mL) of the second solvent, is preferably
1:10.
Preferably, in S2, the second solvent is in toluene, dimethylbenzene, dimethyl sulfoxide, n-butyl alcohol, DMF
One or more compositionss, preferably n-butyl alcohol.
Methyl in atom N, by using doxylamine to react with phenyl chloroformate, is sloughed and is obtained many hilas by the present invention
Quick impurity G, synthetic route is short, and method is easy, and reaction selectivity is high, and reaction condition is gentle, and pollutant are few, and purity is high, and often step is anti-
Yield is answered to be up to more than 80%, economic and environment-friendly, may be used for the impurity quantification during doxylamine succinate produces and quantitative analysis,
Such that it is able to improve the quality standard of doxylamine succinate.
Accompanying drawing explanation
Fig. 1 is the proton nmr spectra of gained doxylamine impurity G of the present invention.
Fig. 2 is the mass spectrum of gained doxylamine impurity G of the present invention.
Detailed description of the invention
Below, by specific embodiment, technical scheme is described in detail.
Embodiment 1
The preparation method of a kind of doxylamine impurity G that the present invention proposes, comprises the steps:
S1, doxylamine adding mix homogeneously in toluene, doxylamine is 1 with the mass volume ratio (g/mL) of toluene:
5, it is subsequently added into sodium hydroxide, doxylamine is 1:4 with the mol ratio of sodium hydroxide, then is placed in ice bath dropping chloro-carbonic acid benzene
Ester, doxylamine is 1:1.5 with the mol ratio of phenyl chloroformate, is warming up to 52 DEG C after dropping, is incubated 4.5h, washes 1 time,
Saturated aqueous common salt washs 1 time, and organic facies is dried, and filters, is spin-dried for, then obtains intermediate product after column chromatography, in column chromatography procedure,
Eluant uses petrol ether/ethyl acetate system, petroleum ether: the volume ratio of ethyl acetate is 10:1；
S2, intermediate product adding mix homogeneously in toluene, intermediate product is 1 with the mass volume ratio (g/mL) of toluene:
5, it is subsequently added into triethylamine, intermediate product is 1:15 with the mol ratio of triethylamine, is warming up to backflow, insulation backflow 2h, then lowers the temperature
To 6 DEG C, sucking filtration, filtrate is spin-dried for, and is dissolved in dichloromethane, is washed to neutrality, adds hydrochloric acid regulation PH to 2 ± 0.5, layering, water layer
Dropping sodium hydrate aqueous solution to pH value is more than 12, after addition dichloromethane extracts 3 times, merges organic layer, anhydrous sodium sulfate
Being dried, filter, filtrate is spin-dried for, and after adding first tertiary ether stirring and dissolving, sucking filtration, filtrate is spin-dried for, and obtains doxylamine impurity G.
Embodiment 2
The preparation method of a kind of doxylamine impurity G that the present invention proposes, comprises the steps:
S1, doxylamine is added mix homogeneously in dimethyl sulfoxide, the mass volume ratio (g/ of doxylamine and dimethyl sulfoxide
ML) being 1:10, be subsequently added into potassium hydroxide, doxylamine is 1:2 with the mol ratio of potassium hydroxide, then is placed in ice bath dropping chlorine
Phenyl formate, doxylamine is 1:1.5 with the mol ratio of phenyl chloroformate, is warming up to 48 DEG C after dropping, is incubated 5.5h, water
Washing 1 time, saturated aqueous common salt washs 1 time, and organic facies is dried, and filters, is spin-dried for, then obtains intermediate product, column chromatography after column chromatography
During, eluant uses petrol ether/ethyl acetate system, petroleum ether: the volume ratio of ethyl acetate is 6:1；
S2, intermediate product is added mix homogeneously in DMF, intermediate product and N, N-dimethyl formyl
The mass volume ratio (g/mL) of amine is 1:15, is subsequently added into sodium hydroxide, and intermediate product is 1:5 with the mol ratio of sodium hydroxide,
It is warming up to backflow, insulation backflow 2.5h, then is cooled to 4 DEG C, sucking filtration, filtrate is spin-dried for, and is dissolved in dichloromethane, is washed to neutrality,
Adding hydrochloric acid regulation PH to 2 ± 0.5, layering, water layer dropping sodium hydrate aqueous solution to pH value is more than 12, adds dichloromethane extraction
After taking 3 times, merging organic layer, anhydrous sodium sulfate is dried, and filters, and filtrate is spin-dried for, after adding first tertiary ether stirring and dissolving, and sucking filtration, filter
Liquid is spin-dried for, and obtains doxylamine impurity G.
Embodiment 3
The preparation method of a kind of doxylamine impurity G that the present invention proposes, comprises the steps:
S1, doxylamine adding mix homogeneously in toluene, doxylamine is 1 with the mass volume ratio (g/mL) of toluene:
6, it is subsequently added into triethylamine, doxylamine is 1:3 with the mol ratio of triethylamine, then is placed in ice bath dropping phenyl chloroformate, many
Hila is quick is 1:1.1 with phenyl chloroformate mol ratio, is warming up to 50 DEG C, is incubated 5h, washes 1 time, saturated food after dropping
Saline washs 1 time, and organic facies is dried, and filters, is spin-dried for, then obtains intermediate product, in column chromatography procedure, eluant after column chromatography
Use petrol ether/ethyl acetate system, petroleum ether: the volume ratio of ethyl acetate is 8:1；
S2, intermediate product is added mix homogeneously in n-butyl alcohol, the mass volume ratio (g/mL) of intermediate product and n-butyl alcohol
For 1:10, being subsequently added into potassium hydroxide, intermediate product is 1:10 with the mol ratio of potassium hydroxide, is warming up to backflow, insulation backflow
2.2h, then be cooled to 5 DEG C, sucking filtration, filtrate is spin-dried for, and is dissolved in dichloromethane, is washed to neutrality, add hydrochloric acid regulation PH to 2 ±
0.5, layering, water layer dropping sodium hydrate aqueous solution to pH value is more than 12, after addition dichloromethane extracts 3 times, merges organic
Layer, anhydrous sodium sulfate is dried, and filters, and filtrate is spin-dried for, and after adding first tertiary ether stirring and dissolving, sucking filtration, filtrate is spin-dried for, and obtains many hilas
Quick impurity G.
Embodiment 4
35.1g doxylamine and 210ml toluene are added in reaction bulb, adds 39.5g triethylamine, the lower dropping of ice bath cooling
22.4g phenyl chloroformate, drips complete, is warming up to 50 DEG C, insulation reaction 5h, washes 1 time, and saturated aqueous common salt washs 1 time, organic
It is dried mutually, filters, be spin-dried for, obtain 47.5g product, cross post, petroleum ether: ethyl acetate=8:1 rinses, obtain producing in the middle of 39.5g
Thing, its yield is 80.8%.
39.5g intermediate product is dissolved in 395ml n-butyl alcohol, adds 58g potassium hydroxide, be warming up to backflow, after backflow 2h,
Being cooled to 5 DEG C, sucking filtration, filtrate is spin-dried for, and is dissolved in dichloromethane, is washed to neutrality, adds hydrochloric acid regulation PH to 2, and layering, water layer adds
Sodium hydrate aqueous solution, regulates PH to 14, after addition dichloromethane extracts 3 times, merges organic layer, and anhydrous sodium sulfate is dried, mistake
Filter, filtrate is spin-dried for, and after adding first tertiary ether stirring and dissolving, sucking filtration, filtrate is spin-dried for, and obtains the doxylamine impurity of 22g white solid state
G, its yield reaches 81.8%.
The assay method of the HPLC purity of doxylamine impurity G is: take doxylamine impurity G appropriate, accurately weighed, adds stream
Dynamic phased soln quantitatively dilution make the solution in every 1ml containing about 1mg, as need testing solution.According to high performance liquid chromatography (in
State's pharmacopeia two annex V D of version in 2015) measure.It is filler with octadecylsilane chemically bonded silica；Triethylamine buffer solution (takes
4mL phosphoric acid, 7mL triethylamine, be diluted with water to 1000mL, with triethylamine regulation pH value to 3.5) and acetonitrile be 80 by volume:
20 mixing are as flowing phase；Flow velocity is 1.0mL/min；Detection wavelength is 262nm；Column temperature is 25 DEG C.It is molten that precision measures test sample
Liquid 10 μ L, injects chromatograph of liquid, 4 times of record chromatogram to main constituent peak retention time, record chromatogram and result.
Being analyzed by embodiment 4 gained doxylamine impurity G, as depicted in figs. 1 and 2, Fig. 1 is institute of the present invention to its result
Obtaining the proton nmr spectra of doxylamine impurity G, Fig. 2 is the mass spectrum of gained doxylamine impurity G of the present invention.By Fig. 1 and Fig. 2
Understand the structure of doxylamine impurity G, with the theoretical construct base of N-methyl-2-[1-phenyl-1-(2-pyridine) ethyoxyl] ethamine
This is consistent, it was demonstrated that present invention synthesis obtains doxylamine impurity G, and purity is the highest.
The above, the only present invention preferably detailed description of the invention, but protection scope of the present invention is not limited thereto,
Any those familiar with the art in the technical scope that the invention discloses, according to technical scheme and
Inventive concept equivalent or change in addition, all should contain within protection scope of the present invention.
Claims (10)
1. the preparation method of a doxylamine impurity G, it is characterised in that comprise the steps:
S1, doxylamine (I) and phenyl chloroformate reaction obtain intermediate product (II)；
The hydrolysis of S2, intermediate product (II) obtains doxylamine impurity G (III)；
The most according to claim 1, the preparation method of doxylamine impurity G, it is characterised in that in S1, doxylamine (I) exist
React with phenyl chloroformate under the conditions of alkalescence, after column chromatography, obtain intermediate product (II).
The preparation method of doxylamine impurity G the most according to claim 1 or claim 2, it is characterised in that in S1, by doxylamine
(I) add mix homogeneously in the first solvent, be subsequently added into the first highly basic, then be placed in ice bath dropping phenyl chloroformate, drip
Heat up after Biing, insulation, washing, it is dried, after column chromatography, obtains intermediate product (II).
4. according to the preparation method of doxylamine impurity G described in any one of claim 1-3, it is characterised in that in S1, many hilas
Quick is 1:1～1.5, preferably 1:1.1 with phenyl chloroformate mol ratio.
5. according to the preparation method of doxylamine impurity G described in any one of claim 1-4, it is characterised in that in S1, many hilas
Quick is 1:5～10, preferably 1:6 with the first solvent mass volume ratio (g/mL)；Preferably, in S1, the first solvent be toluene,
One or more compositionss in dimethylbenzene, dimethyl sulfoxide, n-butyl alcohol, DMF, preferably toluene.
6. according to the preparation method of doxylamine impurity G described in any one of claim 1-5, it is characterised in that in S1, many hilas
Quick is 1:2～4, preferably 1:3 with the first highly basic mol ratio；Preferably, in S1, the first highly basic is sodium hydroxide, hydroxide
One or more compositionss in potassium, triethylamine, preferably triethylamine.
7. according to the preparation method of doxylamine impurity G described in any one of claim 1-6, it is characterised in that in S1, drip
It is warming up to 48～52 DEG C after Biing, is incubated 4.5～5.5h.
8. according to the preparation method of doxylamine impurity G described in any one of claim 1-7, it is characterised in that in S1, column chromatography
During, eluant uses petrol ether/ethyl acetate system；Preferably, petroleum ether: the volume ratio of ethyl acetate is 6～10:1,
It is preferably 8:1.
9. according to the preparation method of doxylamine impurity G described in any one of claim 1-8, it is characterised in that in S2, middle product
Thing (II) hydrolyzes in the basic conditions and obtains doxylamine impurity G；Preferably, in S2, intermediate product (II) is added second molten
Mix homogeneously in agent, is subsequently added into the second highly basic, is warming up to backflow, insulation backflow, then lowers the temperature, sucking filtration, and washing is dried to obtain many
Hila quick impurity G (III)；Preferably, in S2, insulation return time is 2～2.5h；Preferably, in S2, it is cooled to 4～6 DEG C.
The preparation method of doxylamine impurity G the most according to claim 9, it is characterised in that in S2, intermediate product (II)
It is 1:5～15, preferably 1:10 with the mol ratio of the second highly basic；Preferably, in S2, the second highly basic is sodium hydroxide, hydroxide
One or more compositionss in potassium, triethylamine, preferably potassium hydroxide；Preferably, in S2, intermediate product (II) and the
The mass volume ratio (g/mL) of two solvents is 1:5～15, preferably 1:10；Preferably, in S2, the second solvent is toluene, diformazan
One or more compositionss in benzene, dimethyl sulfoxide, n-butyl alcohol, DMF, preferably n-butyl alcohol.
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Citations (1)
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| CN105510512A (en) * | 2016-01-25 | 2016-04-20 | 南京济群医药科技有限公司 | RT-HPLC detection method for related substances of doxylamine succinate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105510512A (en) * | 2016-01-25 | 2016-04-20 | 南京济群医药科技有限公司 | RT-HPLC detection method for related substances of doxylamine succinate |
Non-Patent Citations (4)
| Title |
|---|
| C. L. HOLDER,等: "Mass Spectral Characterization of Doxylamine and its Rhesus Monkey Urinary Metabolites", 《BIOMEDICAL MASS SPECTROMETRY》 * |
| R. A. OLOFSON,等: "USE OF THE VINYLOXYCARBONYL GROUP FOR AMINO PROTECTION IN PEPTIOE SYNTHESIS", 《TETRAHEDRON LETTERS》 * |
| XIAOFENG WANG,等: "Effect of oxidation on amine-based pharmaceutical degradation and N-Nitrosodimethylamine formation", 《WATER RESEARCH》 * |
| 王锋鹏: "《生物碱化学》", 29 February 2008, 化学工业出版社 * |
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