CN109503479A - A kind of naphthoquine phosphate process impurity and its synthetic method - Google Patents
A kind of naphthoquine phosphate process impurity and its synthetic method Download PDFInfo
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- CN109503479A CN109503479A CN201811468485.1A CN201811468485A CN109503479A CN 109503479 A CN109503479 A CN 109503479A CN 201811468485 A CN201811468485 A CN 201811468485A CN 109503479 A CN109503479 A CN 109503479A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/74—Optical detectors
Abstract
The invention discloses a kind of structures for the naphthoquine phosphate process impurity having not been reported shown in formula (I), and it provides a kind of alkylaminomethyl phenol and is converted into corresponding alkyl oxygen methylphenol, or the method that the alkylaminomethyl phenol replaced is converted into substituted alkyl oxygen methylphenol, alkylaminomethyl phenol or substituted alkylaminomethyl phenol are dissolved in alcohol and being reacted with dihalo hydrocarbon and bicarbonate, prepares alkyl oxygen methylphenol or substituted alkyl oxygen methylphenol using good the leaving away property of cyclic mechanism and quaternary ammonium group of quaternary ammonium salt.This method is without using special reactor, and easy to operate without protecting to the phenolic hydroxyl group in substrate, the reagent used is simple and easy to get, substantially reduces reaction step, application value with higher.
Description
Technical field
The present invention relates to a kind of naphthoquine phosphate process impurity and its synthetic methods.
Background technique
Naphthoquine phosphate is the Novel antimalaria medicine after arteannuin medicine, asexual to various plasmodium erythrocyte stages
Body have it is stronger kill effect, be to treat malignant malaria and every other day cruel choice drug with preferable preventive and therapeutic effect.Simultaneously
CN104666300 reports that naphthoquine phosphate is mould to close monospore branch, dermatitis monospore branch is mould, fonsecaea pedrosoi, the small spore of gypsum sample
It is daughter bacteria, star trichophyton gypseum, Trichophyton verrucosum, microsporum canis, bacillus coli, staphylococcus albus, golden yellow
The growth of color staphylococcus, mycobacterium tuberculosis (M. tuberculosis), mycobacterium smegmatis, staphylococcus epidermis has inhibition to make
With naphthoquine phosphate infected with more significant therapeutic effect, mentions staphylococcus aureus, mycobacterium tuberculosis, trichophyta
Show that naphthoquine phosphate is a very promising antibacterial compound in broad spectrum.
The synthesis technology of naphthoquine phosphate declares the standard items pair for needing to use phosphoric acid naphthols related impurities with quality control
According to.Naphthoquine phosphate ethylether impurity is the impurity generated when synthesizing naphthoquine phosphate bulk pharmaceutical chemicals.Naphthols quinoline ethylether is miscellaneous at present
Matter has no its structure of any document report, also reports its synthetic method, therefore naphthols quinoline ethylether impurity structure without pertinent literature
Identification and its synthetic method exploitation value with higher.
For converting corresponding alkyl oxygen methylphenol for alkylaminomethyl phenol, or by substituted alkylaminomethyl
Phenol is converted into the reaction of substituted alkyl oxygen methylphenol, and conventional method reaction step is longer, at least need 4 steps and 4 steps with
On, it will also be longer if there are amino or aminoderivative reaction steps on phenyl ring.Due to alkylaminomethyl phenol or substituted
Phenolic hydroxyl group and benzamido group in alkylaminomethyl phenol molecule all have reactivity, if do not protected to phenolic hydroxyl group,
Target product is hardly resulted in, and reaction process is also further increased to the protection of phenolic hydroxyl group, reduces reaction efficiency, it is therefore desirable to
A kind of method is provided to simplify this reaction process.
Alkylaminomethyl phenol disclosed by the invention is converted into corresponding alkyl oxygen methylphenol, or the alkyl ammonia replaced
The method that methylphenol is converted into substituted alkyl oxygen methylphenol only needs a step, greatly reduces reaction step saving reaction
Time shortens process flow, has very high application value.
Summary of the invention
In view of the above-mentioned problems, the invention discloses a kind of naphthoquine phosphate process impurity and its synthetic methods.
Corresponding alkyl oxygen methylphenol is converted by alkylaminomethyl phenol the present invention provides a kind of, or replace
The method that alkylaminomethyl phenol is converted into substituted alkyl oxygen methylphenol, it is characterised in that: the method includes by alkyl
Aminomethyl phenol or substituted alkylaminomethyl phenol are dissolved in alcohol and reacting with dihalo hydrocarbon and bicarbonate, utilize quaternary ammonium salt
Cyclic mechanism and good the leaving away property of quaternary ammonium group prepare alkyl oxygen methylphenol or substituted alkyl oxygen methylphenol.
Further, the alkylaminomethyl phenol or substituted alkylaminomethyl phenol: dihalo hydrocarbon: bicarbonate
Molar ratio is 1:1-1.2:1-1.5.
Further, the dihalo hydrocarbon is the dihalo hydrocarbon that five yuan or six-membered cyclic quaternary ammonium salt can be formed with secondary amine,
Halogen atom in halogenated hydrocarbons does not include iodine and fluorine.
Further, the dihalo hydrocarbon is selected from Isosorbide-5-Nitrae-dibromobutane, Isosorbide-5-Nitrae-dichloroetane, the bromo- 4- chlorobutane of 1-, 1,
The bromo- 5- chloropentane of pentamethylene bromide, 1,5- dichloropentane, 1-.
Further, the bicarbonate is the bicarbonate that alkalinity is less than sodium phenate.
Further, the bicarbonate is selected from sodium bicarbonate, saleratus, calcium bicarbonate, lithium bicarbonate.
Further, the alcohol is alkylol.
Further, the alcohol is selected from methanol, ethyl alcohol, propyl alcohol, isopropanol, butanol, isobutanol.
Further, the alcohol is added until alkylaminomethyl phenol or substituted alkylaminomethyl phenol can be in room temperatures
The dosage of lower stirring dissolved clarification, alcohol is no more than 1mmol alkylaminomethyl phenol or substituted alkylaminomethyl phenol corresponds to 10mL alcohol.
Further, the reaction temperature is no more than 80 DEG C.
Further, the method further includes following steps:
(1) concentration removes the solvent in reaction solution after the reaction was completed；
(2) product of previous step organic solvent not soluble in water is dissolved；
(3) it is washed with the 1mol/L dilute hydrochloric acid solution with reaction substrate equimolar amounts, collects organic phase；
(4) dry concentration, purifies to get target product.
Further, above-mentioned reaction organic solvent not soluble in water be selected from methylene chloride, chloroform, ethyl acetate,
Toluene, methyl tertiary butyl ether(MTBE).
Further, the alkyl oxygen methylphenol or substituted alkyl oxygen methylphenol have such as formula (IIA) or formula
(IIB) structure shown in:
Wherein: R is alkyl, it is preferable that the alkyl is methyl, ethyl, propyl, isopropyl, butyl.
The present invention also provides a kind of compounds, it is characterised in that: it is a kind of naphthoquine phosphate process impurity, has formula
(I) structure shown in:
It is used to detect the application in naphthoquine phosphate quality as reference substance the present invention also provides aforesaid compound.
The present invention also provides the methods that impurity shown in formula (I) in naphthoquine phosphate is surveyed in detection, and steps are as follows: taking to sample
Product are detected using high performance liquid chromatography, and wherein chromatographic column is C8 column, and Detection wavelength 254nm, mobile phase A is 0.1% trifluoro
Acetic acid aqueous solution, Mobile phase B are 0.1% trifluoroacetic acid acetonitrile solution, gradient elution, type of elution are as follows: 0~5min, 70%A；5
~15min, 70%A；15~35min, 50%A；Preferably, column temperature is 30 DEG C, and sample volume is 10 μ L.
In the present invention, the alkyl includes straight chained alkyl and branched alkyl.
Shown in the reaction mechanism mechanism of reaction that the present invention reacts such as formula (II):
Naphthoquine phosphate free alkali is being used with the dihalo hydrocarbon that can form five yuan or six-membered cyclic quaternary ammonium salt with secondary amine
It is reacted in bicarbonate, since the alkalinity of bicarbonate is less than corresponding sodium phenate, dihalo hydrocarbon is preferential and secondary amine reacts to be formed
Intermediate state 1, intermediate state 1 spontaneously form five yuan or six-membered cyclic quaternary ammonium salt i.e. intermediate state 2 in heating, quaternary ammonium group be preferably from
Group is removed, reflux forms finished product in corresponding alcohol.
The invention discloses a kind of structures of naphthoquine phosphate process impurity having not been reported, and provide a kind of alkyl
Aminomethyl phenol is converted into corresponding alkyl oxygen methylphenol, or the alkylaminomethyl phenol replaced is converted into substituted alkyl
The method of oxygen methylphenol, using good the leaving away property of cyclic mechanism and quaternary ammonium group of quaternary ammonium salt, it is right in the reaction to avoid
Phenolic hydroxyl group is protected, and one-step synthesis method target product is not needed using special reactor, the reagent easy to operate used
It is simple and easy to get, it is not required to be heated at high temperature, substantially reduces reaction step, improve reaction efficiency, meet environmentally protective theory, have
There is higher industrial value.
Obviously, above content according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The specific embodiment of form by the following examples remakes further specifically above content of the invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on above content of the present invention
The technology realized all belongs to the scope of the present invention.
Detailed description of the invention
Fig. 1 is naphthoquine phosphate high-efficient liquid phase chromatogram.
Fig. 2 is naphthoquine phosphate high-efficient liquid phase chromatogram.
Fig. 3 is naphthoquine phosphate high-efficient liquid phase chromatogram.
Fig. 4 is naphthoquine phosphate and naphthoquine phosphate ethylether mixed solution high-efficient liquid phase chromatogram.
Specific embodiment
Raw material, equipment used in the specific embodiment of the invention are known product, are obtained by purchase commercial product.
The synthesis of 1 naphthoquine phosphate ethylether of embodiment
Naphthoquine phosphate free alkali 12.3g is added in the 500mL three-necked flask with condenser and thermometer
(30mmol), sodium bicarbonate 2.78g (33mmol), Isosorbide-5-Nitrae-dibromobutane 6.47g (30mmol) and 300mL ethyl alcohol, rise under stirring
Temperature is reacted 38 hours to flowing back.TLC monitoring display reaction is completed, and concentration of reaction solution sequentially adds methylene chloride 300mL, and 1M is dilute
Hydrochloric acid solution 100mL, mixture stir 20 minutes, liquid separation.Methylene chloride phase anhydrous sodium sulfate dries, filters, and filtrate concentration obtains
Viscous shape solid, crosses column (pure ethyl acetate elution), obtains target product 2.87g, yield 25%.1HNMR (400MHz, MeOD) δ
8.57-8.51 (1H, d) δ 8.29-8.27 (1H, d), δ 7.97-7.94 (1H, m), δ 7.78-7.74 (1H, dd), δ 7.24 (1H,
S), δ 7.04 (1H, s), δ 6.39-6.37 (1H, d), δ 4.61 (2H, s), δ 3.65-3.58 (2H, q), δ 2.74-2.70 (2H,
T), δ 2.62-2.56 (2H, t), δ 1.81-1.72 (4H, m), δ 1.47 (1H, s), δ 1.26-1.21 (3H, t) .MS m/z:
383.1[M+H]+。
The synthesis of 2 2- of embodiment [(methoxyl group) methyl] phenol
2- [(methylamino) methyl] phenol 4.1g is added in the 100mL three-necked flask with condenser and thermometer
(30mmol), saleratus 3.0g (30mmol), Isosorbide-5-Nitrae-dichloroetane 4.19g (33mmol) and 60mL methanol stir lower heating
To reflux, react 24 hours.TLC monitoring display reaction is completed, and concentration of reaction solution sequentially adds methylene chloride 100mL, the dilute salt of 1M
Acid solution 30mL, mixture stir 20 minutes, liquid separation.Methylene chloride phase anhydrous sodium sulfate dries, filters, and column is crossed in filtrate concentration
(petroleum ether: ethyl acetate=5:2 elution), obtains target product 3.52g, yield 85%.1HNMR (400MHz, CDCl3)δ7.01-
6.93 (1H, t), δ 6.80-6.78 (1H, d), δ 6.67-6.58 (2H, m), δ 4.45 (2H, s), (3H, the s) .MS of δ 3.23 m/z:
138.1[M+H]+。
The synthesis of 3 2- of embodiment [(methoxyl group) methyl] phenol
2- [(ethylamino) methyl] phenol 4.53g is added in the 100mL three-necked flask with condenser and thermometer
(30mmol), the bromo- 4- chlorobutane 5.14g (30mmol) of calcium bicarbonate 5.83g (36mmol), 1- and 60mL methanol, rise under stirring
Temperature is reacted 20 hours to flowing back.TLC monitoring display reaction is completed, and concentration of reaction solution sequentially adds methylene chloride 100mL, and 1M is dilute
Hydrochloric acid solution 30mL, mixture stir 20 minutes, liquid separation.Methylene chloride phase anhydrous sodium sulfate dries, filters, and filtrate concentration obtains
Viscous shape solid crosses column (petroleum ether: ethyl acetate=5:2 elution), obtains target product 3.53g, yield 85.1%.1HNMR
(400MHz, CDCl3) δ 7.30-6.98 (1H, m), δ 6.95-6.57 (3H, m), δ 5.67 (1H, bs), δ 4.41 (2H, s), δ
3.37 (3H, s)；MS m/z:138.1[M+H]+。
The synthesis of 4 2- of embodiment [(isopropyl oxygen) methyl] phenol
2- [(the third amino) methyl] phenol 4.96g is added in the 500mL three-necked flask with condenser and thermometer
(30mmol), lithium bicarbonate 2.24g (33mmol), 1, pentamethylene bromide 6.9g (30mmol) and 180mL isopropanol rise under stirring
Temperature is reacted 36 hours to flowing back.The most of reaction of TLC monitoring display is completed, and concentration of reaction solution sequentially adds methylene chloride
60mL, 1M dilute hydrochloric acid solution 30mL, mixture stir 20 minutes, liquid separation.Methylene chloride phase anhydrous sodium sulfate dries, filters, filter
Liquid concentration, obtains viscous shape solid, crosses column (petroleum ether: ethyl acetate=5:2 elution), obtains target product 2.2g, yield 45%.1HNMR (400MHz, DMSO-d6) δ 9.36 (1H, s), δ 7.23-7.20 (1H, d), δ 7.08-7.03 (1H, t), δ 6.79-6.73
(2H, t), δ 4.41 (2H, s), δ 3.70-3.56 (1H, m), δ 1.14-1.12 (6H, d)；MS m/z:167.1[M+H]+。
The synthesis of 5 2- of embodiment [(isopropyl oxygen) methyl] phenol
2- [(isopropylamino) methyl] phenol 4.96g is added in the 250mL three-necked flask with condenser and thermometer
(30mmol), sodium bicarbonate 3.02g (36mmol), 1,5- dichloropentane 5.07g (36mmol) and 180mL isopropanol, under stirring
It is warming up to reflux, is reacted 40 hours.TLC monitoring display reaction is completed, and concentration of reaction solution sequentially adds methylene chloride 100mL, 1M
Dilute hydrochloric acid solution 30mL, mixture stir 20 minutes, liquid separation.Methylene chloride phase anhydrous sodium sulfate dries, filters, filtrate concentration,
Shape solid must be glued, column (petroleum ether: ethyl acetate=5:2 elution) is crossed, obtains target product 2.09g, yield 42%.
6 2- of embodiment [(propoxyl group) methyl] phenol
2- [(i-butylamino) methyl] phenol 5.37g is added in the 500mL three-necked flask with condenser and thermometer
(30mmol), the chloro- pentane 5.56g (30mmol) of sodium bicarbonate 3.02g (36mmol), 1- bromo- 5 and 220mL propyl alcohol, rise under stirring
Temperature is reacted 42 hours to 80 DEG C.TLC monitoring display reaction is completed, and concentration of reaction solution sequentially adds methylene chloride 100mL, and 1M is dilute
Hydrochloric acid solution 30mL, mixture stir 20 minutes, liquid separation.Methylene chloride phase anhydrous sodium sulfate dries, filters, and filtrate concentration obtains
Viscous shape solid crosses column (petroleum ether: ethyl acetate=5:2 elution), obtains target product 2.49g, yield 50%.1HNMR
(400MHz, DMSO-d6) δ: 9.36 (1H, s), δ 7.23-7.20 (1H, d), δ 7.08-7.03 (1H, t), δ 6.79-6.73 (2H,
T), δ 4.41 (2H, s), δ 3.35 (2H, m), δ 1.49 (2H, q), δ 0.99 (3H, t)；MS m/z:167.1[M+H]+。
7 2- of embodiment [(isobutoxy) methyl] phenol
2- [(i-butylamino) methyl] phenol 5.37g is added in the 500mL three-necked flask with condenser and thermometer
(30mmol), sodium bicarbonate 3.78g (45mmol), 1, pentamethylene bromide 6.89g (30mmol) and 300mL isobutanol, under stirring
80 DEG C are warming up to, is reacted 48 hours.TLC monitoring display reaction is completed, and concentration of reaction solution sequentially adds methylene chloride 100mL, 1M
Dilute hydrochloric acid solution 30mL, mixture stir 20 minutes, liquid separation.Methylene chloride phase anhydrous sodium sulfate dries, filters, filtrate concentration,
Shape solid must be glued, column (petroleum ether: ethyl acetate=5:2 elution) is crossed, obtains target product 1.73g, yield 32%.1HNMR
(400MHz, DMSO-d6) δ: 9.36 (1H, s), δ 7.23-7.20 (1H, d), δ 7.08-7.03 (1H, t), δ 6.79-6.73 (2H,
T), δ 4.41 (2H, s), δ 3.30 (2H, d), δ 1.52 (1H, m), (6H, d) the .MS m/z:181.1 of δ 0.91 [M+H]+。
8 2- of embodiment [(butoxy) methyl] phenol
2- [(i-butylamino) methyl] phenol 5.37g is added in the 500mL three-necked flask with condenser and thermometer
(30mmol), sodium bicarbonate 3.78g (45mmol), 1,5- dibromobutane 6.89g (30mmol) and 300mL butanol, rise under stirring
Temperature is reacted 48 hours to 80 DEG C.TLC monitoring display reaction is completed, and concentration of reaction solution sequentially adds methylene chloride 100mL, and 1M is dilute
Hydrochloric acid solution 30mL, mixture stir 20 minutes, liquid separation.Methylene chloride phase anhydrous sodium sulfate dries, filters, and filtrate concentration obtains
Viscous shape solid crosses column (petroleum ether: ethyl acetate=5:2 elution), obtains target product 1.73g, yield 32%.1HNMR
(400MHz, DMSO-d6) δ: 9.36 (1H, s), δ 7.23-7.20 (1H, d), δ 7.08-7.03 (1H, t), δ 6.79-6.73 (2H,
T), δ 4.41 (2H, s), δ 3.35 (2H, d), δ 1.52-1.46 (4H, m), (3H, d) the .MS m/z:181.1 of δ 0.94 [M+H]+。
The detection of 9 naphthoquine phosphate ethylether of embodiment
It is detected by naphthoquine phosphate ethylether of the high performance liquid chromatography to synthesis, the chromatographic condition used is as follows:
Chromatographic column is Agilent C8 column (4.6mm × 250mm；5 μm), detector is UV detector, Detection wavelength 254nm, column
Temperature is 30 DEG C, and sample volume is 10 μ L, and mobile phase A is 0.1% trifluoroacetic acid aqueous solution, and Mobile phase B is 0.1% trifluoroacetic acid acetonitrile
Solution, using gradient elution (0~5min, 70%A；5~15min, 70%A；15~35min, 50%A).Chromatographic results such as Fig. 4
Shown, the peak that wherein retention time is 8.822min is naphthoquine phosphate, and the peak that retention time is 22.007min is phosphoric acid naphthols
Quinoline ethylether.
In conclusion the invention discloses a kind of structures of naphthoquine phosphate process impurity having not been reported, and provide
A kind of alkylaminomethyl phenol is converted into corresponding alkyl oxygen methylphenol, or the alkylaminomethyl phenol replaced is converted into and takes
The method of the alkyl oxygen methylphenol in generation is avoided using good the leaving away property of cyclic mechanism and quaternary ammonium group of quaternary ammonium salt
Phenolic hydroxyl group is protected in reaction, one-step synthesis method target product is not needed using special reactor, easy to operate to make
Reagent is simple and easy to get, is not required to be heated at high temperature, substantially reduces reaction step, improves reaction efficiency, meets environmentally protective
Theory, industrial value with higher.
Claims (16)
1. a kind of convert corresponding alkyl oxygen methylphenol, or the alkylaminomethyl phenol replaced for alkylaminomethyl phenol
The method for being converted into substituted alkyl oxygen methylphenol, it is characterised in that: described method includes following steps: by alkylaminomethyl
Phenol or substituted alkylaminomethyl phenol are dissolved in alcohol, are reacted with dihalo hydrocarbon and bicarbonate, are prepared alkane yloxymethyl
Phenol or substituted alkyl oxygen methylphenol.
2. method according to claim 1, it is characterised in that: the alkylaminomethyl phenol or substituted alkylaminomethyl benzene
Phenol: dihalo hydrocarbon: the molar ratio of bicarbonate is 1:1-1.2:1-1.5.
3. preparation method according to claim 1, it is characterised in that: the dihalo hydrocarbon be can with secondary amine formed five yuan or
The dihalo hydrocarbon of six-membered cyclic quaternary ammonium salt, the halogen atom in halogenated hydrocarbons does not include iodine and fluorine.
4. preparation method according to claim 1 or 3, it is characterised in that: the dihalo hydrocarbon be selected from Isosorbide-5-Nitrae-dibromobutane,
The bromo- 4- chlorobutane of 1,4- dichloroetane, 1-, pentamethylene bromide, 1,5- dichloropentane, the bromo- 5- chloropentane of 1-.
5. preparation method according to claim 1, it is characterised in that: the bicarbonate is the carbon that alkalinity is less than sodium phenate
Sour hydrogen salt.
6. preparation method according to claim 5, it is characterised in that: the bicarbonate is selected from sodium bicarbonate, bicarbonate
Potassium, calcium bicarbonate, lithium bicarbonate.
7. preparation method according to claim 1, it is characterised in that: the alcohol is alkylol.
8. preparation method according to claim 7: it is characterized by: the alcohol be selected from methanol, ethyl alcohol, propyl alcohol, isopropanol,
Butanol, isobutanol.
9. according to claim 1 to preparation method described in 7, it is characterised in that: the alcohol is added until alkylaminomethyl phenol
Or dissolved clarification can be stirred at room temperature in the alkylaminomethyl phenol replaced, the dosage of alcohol is no more than 1mmol alkylaminomethyl phenol
Or the alkylaminomethyl phenol replaced corresponds to 10mL alcohol.
10. preparation method according to claim 1, it is characterised in that: the reaction temperature is no more than 80 DEG C.
11. preparation method according to claim 1, it is characterised in that: the method further includes following steps:
(1) concentration removes the solvent in reaction solution after the reaction was completed；
(2) product of previous step organic solvent not soluble in water is dissolved；
(3) it is washed with the 1mol/L dilute hydrochloric acid solution with reaction substrate equimolar amounts, collects organic phase；
(4) dry concentration, purifies to get target product.
12. preparation method according to claim 11, it is characterised in that: the organic solvent not soluble in water is selected from dichloro
Methane, chloroform, ethyl acetate, toluene, methyl tertiary butyl ether(MTBE).
13. preparation method according to claim 1, it is characterised in that: the alkyl oxygen methylphenol or substituted alkyl
Oxygen methylphenol has the structure as shown in formula (IIA) or formula (IIB):
Wherein: R is alkyl, it is preferable that the alkyl is methyl, ethyl, propyl, isopropyl, butyl.
14. a kind of compound, it is characterised in that: it is a kind of naphthoquine phosphate process impurity, has structure shown in formula (I):
15. compound described in claim 14 is used to detect the application in naphthoquine phosphate quality as reference substance.
16. a kind of method that impurity shown in formula (I) in naphthoquine phosphate is surveyed in detection, it is characterised in that: steps are as follows: taking to sample
Product are detected using high performance liquid chromatography, and wherein chromatographic column is C8 column, and Detection wavelength 254nm, mobile phase A is 0.1% trifluoro
Acetic acid aqueous solution, Mobile phase B are 0.1% trifluoroacetic acid acetonitrile solution, gradient elution, type of elution are as follows: 0~5min, 70%A；5
~15min, 70%A；15~35min, 50%A；Preferably, column temperature is 30 DEG C, and sample volume is 10 μ L.
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