CN106083699B - 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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- C07D213/02—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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Abstract
The invention discloses the preparation methods of doxylamine impurity G a kind of, include the following steps: that doxylamine and phenyl chloroformate react to obtain intermediate product；Intermediate product hydrolyzes to obtain doxylamine impurity G.The preparation method of doxylamine impurity G proposed by the present invention, is reacted by doxylamine with phenyl chloroformate, the methyl on N atom is sloughed to obtain doxylamine impurity G, synthetic route is short, reaction selectivity is high, and raw material is easy to get, and product purity is high, reaction condition is mild, economic and environment-friendly, easy to operate.
Description
Technical field
The present invention relates to pharmaceutical chemistry technical field more particularly to a kind of preparation methods of doxylamine impurity G.
Background technique
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 kind of ethanolamines drug, tool
Have antihistamine effect, cholinolytic effect and a significant sedation, activity is strong and the features such as gastrointestinal side effect is low, be suitable for
A variety of anaphylaxis dermatosis, hay fever, allergic rhinitis, asthmatic bronchitis etc..FDA in October, 1978 ratifies CHATTEM
The doxylamine 25mg tablet of company lists, and is used to help mitigate difficulty falling asleep, becomes within 1979 OTC, the approval of in September, 1996 and
The imitation medicine listing of the approval of in August, 2004 LNK company.The approval of FDA on April 8 in 2013 Diclegis (doxylamine succinate and
Puridoxine hydrochloride) it is oral sustained release piece, the gravid woman for treating bad to conservative processing reaction is subjected to nausea and vomiting.Its
Structural formula is as follows:
The key of doxylamine succinate synthesis essentially consists in the control of impurity, therefore the conjunction of doxylamine succinate impurity
It is had a very important significance at research, can be used for the impurity quantification and quantitative analysis in doxylamine succinate production, from
And the quality standard of doxylamine succinate can be improved.Existing document points out the impurity packet that doxylamine succinate research needs
It includes:
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 are 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 are as follows:
5, doxylamine impurity G, chemical name: N- methyl -2- [1- phenyl -1- (2- pyridine) ethyoxyl] ethamine, structural formula
It is as follows:
It is seldom for the synthesis document report document of doxylamine impurity both at home and abroad at present, especially to doxylamine impurity
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) is pointed out: organic impurities
Detection generally mostly uses HPLC method.HPLC method is such as used, peak area method must be used, specific quantitative approach uses external standard method (impurity
Standard reference), quantified by external standard method is more accurate.
Doxylamine impurity G is the impurity that must be paid close attention in doxylamine quality standard, miscellaneous for doxylamine
The correlative study meaning of matter is very great.Therefore it provides a kind of side of the doxylamine impurity G of simple and effective preparation high-purity
Method is significant for the correlative study of doxylamine impurity.The impurity quantification and determine that it can be used in doxylamine production
The analysis of amount provides important directive significance so as to improve the quality standard of doxylamine for people's masses'safety medication.
Summary of the invention
Technical problems based on background technology, the invention proposes the preparation methods of doxylamine impurity G a kind of, lead to
It crosses doxylamine to react with phenyl chloroformate, the methyl on N atom is sloughed to obtain doxylamine impurity G, method is easy, reaction
Mild condition, raw material are easy to get, and pollutant is few, purity is high, economic and environment-friendly.
The preparation method of doxylamine impurity G proposed by the present invention a kind of, includes the following steps:
S1, doxylamine (I) and phenyl chloroformate react to obtain intermediate product (II)；
S2, intermediate product (II) hydrolysis obtain doxylamine impurity G (III)；
Above-mentioned synthesis flow is as follows:
Preferably, in S1, doxylamine (I) is reacted with phenyl chloroformate under alkaline condition, obtains centre after column chromatography
Product (II).
Preferably, in S1, doxylamine (I) is added in the first solvent and is uniformly mixed, is subsequently added into the first highly basic, then set
Phenyl chloroformate is added dropwise in ice bath, heats up after being added dropwise, keeps the temperature, washs, it is dry, intermediate product is obtained after column chromatography
(Ⅱ)。
Preferably, in S1, the molar ratio of doxylamine and phenyl chloroformate is 1:1~1.5, preferably 1:1.1.
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 toluene, in dimethylbenzene, dimethyl sulfoxide, n-butanol, n,N-Dimethylformamide
One or more kinds of compositions, preferably toluene.
Preferably, in S1, the molar ratio of doxylamine and the first highly basic is 1:2~4, preferably 1:3.
Preferably, in S1, the first highly basic is the combination of one or more of sodium hydroxide, potassium hydroxide, triethylamine
Object, preferably triethylamine.
Preferably, in S1, it is warming up to 48~52 DEG C after being added dropwise, keeps the temperature 4.5~5.5h.
Preferably, in S1, in column chromatography procedure, eluant, eluent 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 obtain doxylamine impurity G (III) under alkaline condition.
Preferably, in S2, intermediate product (II) is added in the second solvent and is uniformly mixed, the second highly basic is subsequently added into, risen
To flowing back, heat preservation flows back temperature, then cools down, and filters, and washing is dried to obtain doxylamine impurity G (III).
Preferably, in S2, heat preservation return time is 2~2.5h.
Preferably, in S2,4~6 DEG C are cooled to.
Preferably, in S2, the molar ratio of intermediate product (II) and the second highly basic is 1:5~15, preferably 1:10.
Preferably, in S2, the second highly basic is the combination of one or more of sodium hydroxide, potassium hydroxide, triethylamine
Object, preferably potassium hydroxide.
Preferably, in S2, the mass volume ratio (g/mL) of intermediate product (II) and the second solvent is 1:5~15, preferably
1:10.
Preferably, in S2, the second solvent is toluene, in dimethylbenzene, dimethyl sulfoxide, n-butanol, n,N-Dimethylformamide
One or more kinds of compositions, preferably n-butanol.
The present invention is reacted by using doxylamine with phenyl chloroformate, and the methyl on N atom is sloughed to obtain more hilas
Quick impurity G, synthetic route is short, and method is easy, and reaction selectivity is high, and reaction condition is mild, and pollutant is few, purity is high, and every step is anti-
Yield is answered to be up to 80% or more, it is economic and environment-friendly, it can be used for impurity quantification and quantitative analysis in doxylamine succinate production,
So as to improve the quality standard of doxylamine succinate.
Detailed description of the invention
Fig. 1 is the nuclear magnetic resonance spectroscopy of present invention gained doxylamine impurity G.
Fig. 2 is the mass spectrogram of present invention gained doxylamine impurity G.
Specific embodiment
In the following, technical solution of the present invention is described in detail by specific embodiment.
Embodiment 1
The preparation method of doxylamine impurity G proposed by the present invention a kind of, includes the following steps:
S1, it will be uniformly mixed in doxylamine addition toluene, the mass volume ratio (g/mL) of doxylamine and toluene is 1:
5, it is subsequently added into sodium hydroxide, the molar ratio of doxylamine and sodium hydroxide is 1:4, then is placed in dropwise addition chloro-carbonic acid benzene in ice bath
The molar ratio of ester, doxylamine and phenyl chloroformate is 1:1.5, and 52 DEG C are warming up to after being added dropwise, and keeps the temperature 4.5h, is washed 1 time,
Saturated common salt water washing 1 time, organic phase dries, filters, and is spin-dried for, and then obtains intermediate product after column chromatography, in column chromatography procedure,
Eluant, eluent uses petrol ether/ethyl acetate system, petroleum ether: the volume ratio of ethyl acetate is 10:1；
S2, it will be uniformly mixed in intermediate product addition toluene, the mass volume ratio (g/mL) of intermediate product and toluene is 1:
5, it is subsequently added into triethylamine, the molar ratio of intermediate product and triethylamine is 1:15, is warming up to reflux, and heat preservation flows back 2h, then cools down
It to 6 DEG C, filters, filtrate is spin-dried for, is dissolved in methylene chloride, is washed to neutrality, and hydrochloric acid is added to adjust PH to 2 ± 0.5, layering, water layer
It is 12 or more that sodium hydrate aqueous solution to pH value, which is added dropwise, after being added methylene chloride extraction 3 times, merges organic layer, anhydrous sodium sulfate
It dries, filters, filtrate is spin-dried for, and after the tertiary ether stirring and dissolving of first is added, filters, and filtrate is spin-dried for, and obtains doxylamine impurity G.
Embodiment 2
The preparation method of doxylamine impurity G proposed by the present invention a kind of, includes the following steps:
S1, doxylamine is added to uniformly mixed in dimethyl sulfoxide, the mass volume ratio (g/ of doxylamine and dimethyl sulfoxide
ML it is) 1:10, is subsequently added into potassium hydroxide, the molar ratio of doxylamine and potassium hydroxide is 1:2, then is placed in ice bath and chlorine is added dropwise
The molar ratio of phenyl formate, doxylamine and phenyl chloroformate is 1:1.5, and 48 DEG C are warming up to after being added dropwise, and keeps the temperature 5.5h, water
It washes 1 time, saturated common salt water washing 1 time, organic phase dries, filters, and is spin-dried for, and intermediate product, column chromatography are then obtained after column chromatography
In the process, eluant, eluent uses petrol ether/ethyl acetate system, petroleum ether: the volume ratio of ethyl acetate is 6:1；
S2, intermediate product is added to uniformly mixed in n,N-Dimethylformamide, 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 the molar ratio of intermediate product and sodium hydroxide is 1:5,
It is warming up to reflux, heat preservation reflux 2.5h, then is cooled to 4 DEG C, is filtered, filtrate is spin-dried for, is dissolved in methylene chloride, it is washed to neutrality,
Hydrochloric acid is added to adjust PH to 2 ± 0.5, layering, it is 12 or more that sodium hydrate aqueous solution to pH value, which is added dropwise, in water layer, and methylene chloride extraction is added
After taking 3 times, merge organic layer, anhydrous sodium sulfate dries, filters, and filtrate is spin-dried for, and after the tertiary ether stirring and dissolving of first is added, filters, filter
Liquid is spin-dried for, and obtains doxylamine impurity G.
Embodiment 3
The preparation method of doxylamine impurity G proposed by the present invention a kind of, includes the following steps:
S1, it will be uniformly mixed in doxylamine addition toluene, the mass volume ratio (g/mL) of doxylamine and toluene is 1:
6, it is subsequently added into triethylamine, the molar ratio of doxylamine and triethylamine is 1:3, then is placed in ice bath and phenyl chloroformate is added dropwise, more
The quick molar ratio with phenyl chloroformate of hila is 1:1.1, and 50 DEG C are warming up to after being added dropwise, keeps the temperature 5h, is washed 1 time, saturation food
Salt water washing 1 time, organic phase dries, filters, and is spin-dried for, and then obtains intermediate product after column chromatography, in column chromatography procedure, eluant, eluent
Using petrol ether/ethyl acetate system, petroleum ether: the volume ratio of ethyl acetate is 8:1；
S2, intermediate product is added to uniformly mixed in n-butanol, the mass volume ratio (g/mL) of intermediate product and n-butanol
For 1:10, it is subsequently added into potassium hydroxide, the molar ratio of intermediate product and potassium hydroxide is 1:10, is warming up to reflux, heat preservation flows back
2.2h, then be cooled to 5 DEG C is filtered, and filtrate is spin-dried for, is dissolved in methylene chloride, is washed to neutrality, add hydrochloric acid adjust PH to 2 ±
0.5, layering, it is 12 or more that sodium hydrate aqueous solution to pH value, which is added dropwise, in water layer, after being added methylene chloride extraction 3 times, is merged organic
Layer, anhydrous sodium sulfate dry, filter, and filtrate is spin-dried for, and after the tertiary ether stirring and dissolving of first is added, filter, and filtrate is spin-dried for, and obtains more hilas
Quick impurity G.
Embodiment 4
35.1g doxylamine and 210ml toluene are added in reaction flask, 39.5g triethylamine is added, ice bath cooling is lower to be added dropwise
22.4g phenyl chloroformate, is added dropwise, and is warming up to 50 DEG C, insulation reaction 5h, washes 1 time, saturated common salt water washing 1 time, organic
Mutually dry, filter, be spin-dried for, obtain 47.5g product, cross column, petroleum ether: ethyl acetate=8:1 is rinsed, and obtains producing among 39.5g
Object, yield 80.8%.
39.5g intermediate product is dissolved in 395ml n-butanol, 58g potassium hydroxide is added, is warming up to reflux, after the 2h that flows back,
5 DEG C are cooled to, is filtered, filtrate is spin-dried for, is dissolved in methylene chloride, is washed to neutrality, and hydrochloric acid is added to adjust PH to 2, layering, and water layer adds
Sodium hydrate aqueous solution adjusts PH to 14, after being added methylene chloride extraction 3 times, merges organic layer, anhydrous sodium sulfate is dry, mistake
Filter, filtrate are spin-dried for, and after the tertiary ether stirring and dissolving of first is added, filter, and filtrate is spin-dried for, and obtains the doxylamine impurity of 22g white solid state
G, yield is up to 81.8%.
The measuring method of the HPLC purity of doxylamine impurity G are as follows: take doxylamine impurity G appropriate, it is accurately weighed, add stream
Dynamic phased soln simultaneously quantifies the solution for diluting and being made in every 1ml containing about 1mg, as test solution.According to high performance liquid chromatography (in
Two V D of annex of state's pharmacopeia version in 2015) measurement.It is filler with octadecylsilane chemically bonded silica；Triethylamine buffer solution (takes
4mL phosphoric acid, 7mL triethylamine, are diluted with water to 1000mL, with triethylamine adjust pH value to 3.5) and acetonitrile be by volume 80:
20 mixing are used as mobile 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
10 μ L of liquid injects liquid chromatograph, 4 times of record chromatogram to principal component peak retention time, records chromatogram and result.
4 gained doxylamine impurity G of embodiment is analyzed, result is as depicted in figs. 1 and 2, and Fig. 1 is institute of the present invention
The nuclear magnetic resonance spectroscopy of doxylamine impurity G is obtained, Fig. 2 is the mass spectrogram of present invention gained doxylamine impurity G.By Fig. 1 and Fig. 2
Know the structure of doxylamine impurity G, the theoretical construct base with N- methyl -2- [1- phenyl -1- (2- pyridine) ethyoxyl] ethamine
This is consistent, it was demonstrated that the present invention synthesizes to obtain doxylamine impurity G, and purity is very high.
The foregoing is only a preferred embodiment of the present invention, but scope of protection of the present invention is not limited thereto,
Anyone skilled in the art in the technical scope disclosed by the present invention, according to the technique and scheme of the present invention and its
Inventive concept is subject to equivalent substitution or change, should be covered by the protection scope of the present invention.
Claims (20)
1. a kind of preparation method of doxylamine impurity G, which comprises the steps of:
S1, doxylamine (I) and phenyl chloroformate react to obtain intermediate product (II), specifically, doxylamine (I) is added the
It is uniformly mixed in one solvent, is subsequently added into the first highly basic, then be placed in ice bath and phenyl chloroformate is added dropwise, heats up after being added dropwise,
Heat preservation is washed, dry, obtains intermediate product (II) after column chromatography, wherein the first solvent is toluene, dimethylbenzene, dimethyl sulfoxide, just
One or more of butanol, n,N-Dimethylformamide composition, the first highly basic are sodium hydroxide, potassium hydroxide, three
One or more of ethamine composition；
S2, intermediate product (II) hydrolysis obtain doxylamine impurity G (III), specifically, it is molten that intermediate product (II) is added second
It is uniformly mixed in agent, is subsequently added into the second highly basic, be warming up to reflux, heat preservation reflux, then cool down, filter, washing is dried to obtain more
The quick impurity G (III) of hila, wherein the second highly basic is the combination of one or more of sodium hydroxide, potassium hydroxide, triethylamine
Object, the second solvent are one or more of toluene, dimethylbenzene, dimethyl sulfoxide, n-butanol, n,N-Dimethylformamide group
Close object；
2. the preparation method of doxylamine impurity G according to claim 1, which is characterized in that in S1, doxylamine and chloromethane
The molar ratio of acid phenenyl ester is 1:1~1.5.
3. the preparation method of doxylamine impurity G according to claim 1, which is characterized in that in S1, doxylamine and chloromethane
The molar ratio of acid phenenyl ester is 1:1.1.
4. the preparation method of any one of -3 doxylamine impurity G according to claim 1, which is characterized in that in S1, more hilas
The quick mass volume ratio with the first solvent is 1g:5~10mL.
5. the preparation method of any one of -3 doxylamine impurity G according to claim 1, which is characterized in that in S1, more hilas
The quick mass volume ratio with the first solvent is 1g:6mL.
6. the preparation method of any one of -3 doxylamine impurity G according to claim 1, which is characterized in that in S1, first is molten
Agent is toluene.
7. the preparation method of any one of -3 doxylamine impurity G according to claim 1, which is characterized in that in S1, more hilas
The quick molar ratio with the first highly basic is 1:2~4.
8. the preparation method of any one of -3 doxylamine impurity G according to claim 1, which is characterized in that in S1, more hilas
The quick molar ratio with the first highly basic is 1:3.
9. the preparation method of any one of -3 doxylamine impurity G according to claim 1, which is characterized in that in S1, the last the first
Alkali is triethylamine.
10. the preparation method of any one of -3 doxylamine impurity G according to claim 1, which is characterized in that in S1, be added dropwise
After be warming up to 48~52 DEG C, keep the temperature 4.5~5.5h.
11. the preparation method of any one of -3 doxylamine impurity G according to claim 1, which is characterized in that in S1, column layer
During analysis, eluant, eluent uses petrol ether/ethyl acetate system.
12. the preparation method of doxylamine impurity G according to claim 11, which is characterized in that petroleum ether: ethyl acetate
Volume ratio is 6~10:1.
13. the preparation method of any one of -3 doxylamine impurity G according to claim 1, which is characterized in that in S2, heat preservation
Return time is 2~2.5h.
14. the preparation method of any one of -3 doxylamine impurity G according to claim 1, which is characterized in that in S2, cooling
To 4~6 DEG C.
15. the preparation method of the 3 doxylamine impurity G according to claim 1, which is characterized in that in S2, intermediate product (II)
Molar ratio with the second highly basic is 1:5~15.
16. the preparation method of doxylamine impurity G according to claim 15, which is characterized in that in S2, intermediate product (II)
Molar ratio with the second highly basic is 1:10.
17. the preparation method of the 3 doxylamine impurity G according to claim 1, which is characterized in that in S2, the second highly basic is hydrogen
Potassium oxide.
18. the preparation method of the 3 doxylamine impurity G according to claim 1, which is characterized in that in S2, intermediate product (II)
Mass volume ratio with the second solvent is 1g:5~15mL.
19. the preparation method of the 8 doxylamine impurity G according to claim 1, which is characterized in that in S2, intermediate product (II)
Mass volume ratio with the second solvent is 1g:10mL.
20. the preparation method of the 3 doxylamine impurity G according to claim 1, which is characterized in that in S2, the second solvent is positive
Butanol.
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