CN115703715A - Central control and finished product analysis method for sunscreen agent A-Plus - Google Patents
Central control and finished product analysis method for sunscreen agent A-Plus Download PDFInfo
- Publication number
- CN115703715A CN115703715A CN202110939608.0A CN202110939608A CN115703715A CN 115703715 A CN115703715 A CN 115703715A CN 202110939608 A CN202110939608 A CN 202110939608A CN 115703715 A CN115703715 A CN 115703715A
- Authority
- CN
- China
- Prior art keywords
- plus
- finished product
- central control
- prepared
- esterification
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000004458 analytical method Methods 0.000 title claims abstract description 28
- 239000000516 sunscreening agent Substances 0.000 title claims abstract description 24
- 238000005886 esterification reaction Methods 0.000 claims abstract description 47
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- 238000005859 coupling reaction Methods 0.000 claims abstract description 39
- 238000000034 method Methods 0.000 claims abstract description 27
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 20
- WAVOOWVINKGEHS-UHFFFAOYSA-N 3-(diethylamino)phenol Chemical compound CCN(CC)C1=CC=CC(O)=C1 WAVOOWVINKGEHS-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000002425 crystallisation Methods 0.000 claims abstract description 17
- 230000008025 crystallization Effects 0.000 claims abstract description 17
- 230000032050 esterification Effects 0.000 claims abstract description 17
- 238000001953 recrystallisation Methods 0.000 claims abstract description 17
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 claims abstract description 15
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000002253 acid Substances 0.000 claims abstract description 14
- 239000002994 raw material Substances 0.000 claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 claims abstract description 8
- 239000000047 product Substances 0.000 claims description 69
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 63
- 239000000523 sample Substances 0.000 claims description 35
- 239000007788 liquid Substances 0.000 claims description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 12
- 239000012488 sample solution Substances 0.000 claims description 11
- 238000004587 chromatography analysis Methods 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 8
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 7
- 239000011541 reaction mixture Substances 0.000 claims description 7
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 230000000475 sunscreen effect Effects 0.000 claims description 5
- 238000003786 synthesis reaction Methods 0.000 claims description 5
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000012153 distilled water Substances 0.000 claims description 4
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 229940078552 o-xylene Drugs 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 239000003643 water by type Substances 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims 1
- 238000001514 detection method Methods 0.000 abstract description 10
- 238000004817 gas chromatography Methods 0.000 abstract description 5
- 239000000243 solution Substances 0.000 description 29
- 239000013068 control sample Substances 0.000 description 12
- 239000012086 standard solution Substances 0.000 description 10
- GLDQAMYCGOIJDV-UHFFFAOYSA-N 2,3-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC(O)=C1O GLDQAMYCGOIJDV-UHFFFAOYSA-N 0.000 description 9
- 239000012535 impurity Substances 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- 238000011084 recovery Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 230000008569 process Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000007086 side reaction Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000002537 cosmetic Substances 0.000 description 3
- FDATWRLUYRHCJE-UHFFFAOYSA-N diethylamino hydroxybenzoyl hexyl benzoate Chemical compound CCCCCCOC(=O)C1=CC=CC=C1C(=O)C1=CC=C(N(CC)CC)C=C1O FDATWRLUYRHCJE-UHFFFAOYSA-N 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- BHSHHNNBVMXJNZ-UHFFFAOYSA-N 2-(diethylamino)ethyl 1-(3-methylbutyl)cyclohexane-1-carboxylate Chemical compound CCN(CC)CCOC(=O)C1(CCC(C)C)CCCCC1 BHSHHNNBVMXJNZ-UHFFFAOYSA-N 0.000 description 1
- YOIQWFZSLGRZJX-UHFFFAOYSA-N 2-(diethylamino)phenol Chemical compound CCN(CC)C1=CC=CC=C1O YOIQWFZSLGRZJX-UHFFFAOYSA-N 0.000 description 1
- TYYHDKOVFSVWON-UHFFFAOYSA-N 2-butyl-2-methoxy-1,3-diphenylpropane-1,3-dione Chemical compound C=1C=CC=CC=1C(=O)C(OC)(CCCC)C(=O)C1=CC=CC=C1 TYYHDKOVFSVWON-UHFFFAOYSA-N 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 239000004904 UV filter Substances 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000003712 anti-aging effect Effects 0.000 description 1
- 230000001153 anti-wrinkle effect Effects 0.000 description 1
- 229960005193 avobenzone Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 229960001630 diethylamino hydroxybenzoyl hexyl benzoate Drugs 0.000 description 1
- AKNXMRHLLPIDLY-UHFFFAOYSA-N diethylamino hydroxybenzoyl hexyl benzoate Chemical compound CCCCCCOC(=O)C1=CC=CC=C1C(=O)C1=CC=CC(N(CC)CC)=C1O AKNXMRHLLPIDLY-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000011165 process development Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Images
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a central control and finished product analysis method of a sun-screening agent A-Plus. 3-diethylaminophenol and phthalic anhydride are used as raw materials, an intermediate 4-diethylaminoketonic acid is prepared through coupling reaction, and the 4-diethylaminoketonic acid and n-hexanol are subjected to esterification reaction to prepare A-Plus. Wherein, before the A-Plus finished product is prepared, a sample obtained at one or more stages of a coupling reaction stage, an esterification reaction stage, crystallization after esterification and recrystallization stage or the degree of reaction progress or the A-Plus purity of the prepared A-Plus is analyzed by high performance liquid chromatography, thereby not only realizing the on-line rapid detection in the production process of the A-Plus, but also detecting the quality of the prepared A-Plus. The method for analyzing the quality of the A-Plus and the finished product has high precision and good reproducibility, and avoids the problem of poor reproducibility caused by using a gas chromatography.
Description
Technical Field
The invention belongs to the technical field of chemical analysis and detection, and particularly relates to a sun-screening agent A-Plus central control and finished product analysis method.
Background
Diethylamino hydroxybenzoyl hexyl benzoate (Uvinul-a Plus, abbreviated as a-Plus) is an organic compound capable of absorbing UVA, a novel UVA (long-wave ultraviolet, UVA contains two bands of UVA1 (340-400 nm) and UVA2 (320-340 nm)) absorbent developed by BASF corporation, is marketed under the trade name Uvinul a Plus, and has the following structural formula:
the A-Plus absorbs UV light up to 400nm, with the UV absorbance being greatest for a wavelength of 354 nm. The ultraviolet absorption waveband of A-Plus is similar to that of the traditional butyl methoxy dibenzoyl methane (AVB), but the protection of UVA1 waveband (340-400 nm) is emphasized, the photochemical stability is good, the compound property with other grease is good, and the A-Plus can be widely used in cosmetics as a sun-screening agent. The product has reliable and long-lasting anti-aging, anti-wrinkle and anti-skin cancer effects, and can be easily combined with other organic and inorganic UV filters for use in sunscreen and other cosmetics.
Currently, the U.S. Food and Drug Administration (FDA), the economic council of the european union (EEC) and the ministry of health in china stipulate that the maximum addition limit (mass fraction) in cosmetics is 10%. The BASF company concluded that a-Plus plays a role in sunscreen products including: the absorption effect on UVA1 is high; the protective effect on free radicals generated by ultraviolet rays is very strong; the SPF value of the UVB sun-screening ingredients can be improved; good photostability, and long-term efficacy.
The reaction in the synthesis process of the A-Plus is complex, the by-products in the synthesis process directly influence the accuracy of a determination structure, the detection time is long, and the production efficiency of the A-Plus is seriously influenced, so the central control analysis of the synthesis of the A-Plus is very critical, and the content determination in the product quality is also very critical.
For the preparation of A-Plus at present, the quality of a finished product is determined by BASF by adopting a GC area percentage method, and the reproducibility and the stability of the method are poor.
Therefore, the research on the rapid and accurate A-Plus central control and finished product detection is urgently needed, and the method has important significance on the production and process development of the A-Plus.
Disclosure of Invention
In order to overcome the problems, the inventor of the invention researches the preparation of the A-Plus and the control and finished product quality analysis method thereof, and researches the control and finished product analysis method of the sunscreen agent A-Plus. 3-diethylaminophenol and phthalic anhydride are used as raw materials, an intermediate 4-diethylaminoketonic acid is prepared through coupling reaction, and the 4-diethylaminoketonic acid and n-hexanol are subjected to esterification reaction to prepare A-Plus. Wherein, before the A-Plus finished product is prepared, a sample obtained at one or more stages of a coupling reaction stage, an esterification reaction stage, crystallization after esterification and recrystallization stage or the degree of reaction progress or the A-Plus purity of the prepared A-Plus is analyzed by high performance liquid chromatography, thereby not only realizing the on-line rapid detection in the production process of the A-Plus, but also detecting the quality of the prepared A-Plus. The method for analyzing the quality of the A-Plus and the finished product has high precision and good reproducibility, and can avoid the problem of poor reproducibility caused by using a gas chromatography, thereby completing the invention.
Specifically, the present invention aims to provide the following:
in one aspect, there is provided a method of making a sunscreen a-Plus, the method comprising: 3-diethylaminophenol and phthalic anhydride are used as raw materials, an intermediate 4-diethylaminoketonic acid is prepared through coupling reaction, the 4-diethylaminoketonic acid is esterified with n-hexanol to obtain an esterification reaction mixture, and the sunscreen agent A-Plus is obtained through purification.
In another aspect, a method for central control and analysis of finished sunscreen agent a-Plus is provided, wherein the method is performed in the method for preparing a-Plus according to the first aspect, and preferably, a sample obtained in one or more stages including a coupling reaction stage, an esterification reaction stage, crystallization after esterification, and recrystallization stage after esterification before a finished sunscreen agent a-Plus is prepared, and the sunscreen agent a-Plus are taken as samples to be tested, and the degree of reaction progress or purity of a-Plus is determined.
The invention has the advantages that:
(1) According to the preparation method of the sunscreen agent A-Plus, the yield of the prepared A-Plus is more than 92%.
(2) The sunscreen agent A-Plus central control and finished product analysis method provided by the invention has high precision and good reproducibility, and solves the problem of poor reproducibility caused by using a gas chromatography.
(3) The sunscreen agent A-Plus central control and finished product analysis method provided by the invention not only realizes online rapid detection in the production process of A-Plus, comprehensively and accurately reflects the content of impurities contained in the central control solution to be detected, detects the degree of reaction or provides indexes for the quality of the prepared A-Plus, but also can directly detect the quality of the prepared A-Plus, is suitable for batch and rapid analysis, and has very strong practicability.
Drawings
FIG. 1 shows the HPLC spectrum in example 1;
FIG. 2 shows a liquid chromatogram of a liquid to be tested in DHBA in example 2;
FIG. 3 shows a liquid chromatogram of the controlled test solution in A-Plus in example 2;
FIG. 4 shows a linear standard curve in example 4;
FIG. 5 shows a liquid chromatogram of the finished product A-Plus to be tested in comparative example 1.
Detailed Description
The invention is explained in more detail below with reference to the figures and examples. The features and advantages of the present invention will become more apparent from the description.
The word "exemplary" is used exclusively herein to mean "serving as an example, embodiment, or illustration. Any embodiment described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments. While the various aspects of the embodiments are presented in drawings, the drawings are not necessarily drawn to scale unless specifically indicated.
In one aspect, the invention provides a method for preparing a sunscreen a-Plus, the method comprising: 3-diethylaminophenol and phthalic anhydride are used as raw materials, an intermediate 4-diethylaminoketonic acid is prepared through coupling reaction, the 4-diethylaminoketonic acid is esterified with n-hexanol, and the sunscreen agent A-Plus is obtained through purification.
Further, one of the raw materials for the coupling reaction is 3-diethylaminophenol having CAS number 91-68-9, also referred to as m-diethylaminophenol, or m-hydroxy-N, N-diethylaniline, and the other raw material phthalic anhydride, and an aromatic hydrocarbon compound is used as a reaction solvent, the aromatic hydrocarbon compound is preferably one or more selected from benzonitrile, toluene, ethylbenzene, o-xylene, m-xylene, p-xylene, and chlorobenzene, and more preferably toluene.
According to the invention, the aromatic hydrocarbon compound is used as an inert solvent and does not react with the coupling reaction raw material, the reaction system is ensured to be homogeneous, the reaction is favorably carried out at a constant speed, and the content of impurities generated by the reaction is low.
According to the invention, the molar weight ratio of the 3-diethylaminophenol, the phthalic anhydride and the aromatic hydrocarbon compound is 1 (1.01-2): (1.5-5.0), preferably 1 (1.05-1.5): (2.0 to 4.0), more preferably 1 (1.1 to 1.3): (2.5-2.6).
In the present invention, an excess of one of the starting materials is selected in order to complete the reaction, preferably a slight excess of phthalic anhydride due to the presence of decomposition of phthalic anhydride; meanwhile, the amount of the aromatic hydrocarbon compound used in the reaction cannot be too large, so that the burden of post-treatment is avoided, but the amount of the aromatic hydrocarbon compound used in the reaction cannot be too small, so that the raw material of the coupling reaction cannot be completely dissolved in the reaction solvent, and the reaction is not uniform.
Further, the reaction is carried out in an inert gas, so that the reaction is continuously and stably generated. The inert gas includes a rare gas or nitrogen, preferably nitrogen which is inexpensive and readily available.
According to the invention, the coupling reaction is carried out at a reaction temperature of 90 to 130 ℃, preferably 100 to 120 ℃ and more preferably 110 to 116 ℃.
Wherein, the reaction temperature is too high, the reaction is too violent, and more side reactions are also initiated; the reaction temperature is too low, the reaction time is prolonged, side reactions may occur, the side reactions are less in the above reaction temperature range, the reaction is stable, and the selectivity of the obtained 4-diethylamino keto acid is high.
In the present invention, the coupling reaction is controlled to have a reaction time of 10 to 20 hours, preferably 12 to 18 hours, for example 15 to 16 hours.
According to the invention, the reaction time is too short and the reaction is incomplete; the reaction time is too long, which not only does not improve the selectivity of 4-diethylaminoketoacid but also may cause side reactions, and from an economic viewpoint, it is preferable to control the reaction time for coupling to 10 to 20 hours.
Optionally, after the reaction is finished, crystallizing and recrystallizing the product of the reaction to obtain the intermediate 4-diethylamino keto acid required by the subsequent esterification reaction.
According to the invention, the reaction for preparing the intermediate 4-diethylamino keto acid by the coupling reaction is shown as the formula (1):
further, the solvent used for the esterification reaction of the intermediate 4-diethylamino keto acid and n-hexanol is preferably one or more selected from concentrated sulfuric acid, tetrahydrofuran, dichloroethane and toluene, and more preferably concentrated sulfuric acid.
In the invention, the concentrated sulfuric acid is used as a catalyst and a dehydrating agent to promote the reaction.
According to the invention, the weight ratio of the 4-diethylaminoketonic acid to the n-hexanol to the solvent is (1-6): (8-15): 1, preferably (2 to 5): (10-13): 1, more preferably (3.6 to 4.0): (12 to 12.5): 1.
wherein an excess of inexpensive n-hexanol is used to increase the utilization of the expensive 4-diethylaminoketoacid and to reduce the decomposition of the A-Plus product.
In the present invention, the esterification reaction temperature is from 100 to 130 ℃, preferably from 105 to up to
120 ℃ and more preferably 108 to 110 ℃.
Further, the reaction is efficiently and stably carried out by controlling the degree of vacuum of the esterification reaction, which is-2 to 2MPa, preferably-1 to 1MPa, for example-0.086 to 0.094MPa.
According to the invention, the esterification reaction is stopped when the content of 4-diethylaminoketoacid is less than or equal to 0.5% (HPLC), and the reaction time is about 6h.
And after the reaction is finished, purifying the esterification reaction product by washing, crystallizing and recrystallizing to obtain the A-Plus finished product.
According to the invention, the esterification reaction for the preparation of A-Plus takes place as shown in formula (2):
on the other hand, according to the sunscreen agent A-Plus central control and finished product analysis method provided by the invention, the central control and finished product analysis are carried out in the preparation method of the A-Plus described in the first aspect, preferably, a sample obtained in one or more stages including a coupling reaction stage, an esterification reaction stage, crystallization after esterification and recrystallization stages before a finished product of the A-Plus is prepared and the sunscreen agent A-Plus are taken as samples to be tested, and the degree of reaction progress or the purity of the A-Plus is measured.
Further, the method adopts high performance liquid chromatography for purity determination, and comprises the following steps:
In step 1, the sample solution to be tested may be a central control solution to be tested prepared from a sample obtained in one or more stages of a coupling reaction stage, an esterification reaction stage, crystallization after esterification, and recrystallization before a finished product of a-Plus is prepared, or may be an a-Plus finished product solution to be tested prepared from a finally obtained a-Plus by a synthesis reaction.
The A-Plus is prepared by taking 3-diethylaminophenol and phthalic anhydride as raw materials, performing coupling reaction to obtain an intermediate 4-diethylaminoketo acid, performing esterification reaction on the 4-diethylaminoketo acid and n-hexanol, and performing washing, crystallization and recrystallization.
In the invention, when the sample solution to be detected is the middle control solution to be detected, the sample is taken in a coupling reaction stage, an esterification reaction stage, a crystallization stage after esterification or a recrystallization stage and is prepared; and when the sample to be detected is the A-Plus finished product liquid to be detected, preparing the A-Plus finished product prepared by the reaction.
Furthermore, when the sample in the coupling reaction stage is used for preparing the central control solution to be detected, the 4-diethylamino ketonic acid is slowly separated out in a solid form in the process to form a solid-liquid mixed sample, the solid in the solid is required to be dissolved, the dissolved central control sample is ensured to be in a uniform phase, and the influence on the central control analysis is avoided.
Through a large number of experiments, the inventor finds that dimethyl sulfoxide is the best choice for dissolving solids and insoluble substances in a sample, and a solvent such as N-N-dimethylformamide can produce similar effects, but dimethyl sulfoxide can completely dissolve the solids and the insoluble substances in a control sample in the coupling reaction stage of A-Plus, so that the control sample is in a uniform phase, and most importantly, no interference is generated in the measurement process.
Wherein, the use amount of dimethyl sulfoxide can not be too little, otherwise can not dissolve the impurity in the central control sample esterification reaction mixture completely, and certainly its use amount also can not be too much, avoids causing the influence to the central control analysis, embodies specifically: during chromatographic analysis, because dimethyl sulfoxide peaks on a liquid phase and the peak-off time of the dimethyl sulfoxide is relatively close to that of the coupling reaction raw material 3-diethylaminophenol, the large dosage of the dimethyl sulfoxide peaks can cause the excessive dimethyl sulfoxide peaks, and further the peak-off of the 3-diethylaminophenol is interfered.
Preferably, the volume ratio of the dimethyl sulfoxide to the coupling reaction stage sample, i.e. to the coupling reaction mixture taken in the reaction stage of 3-diethylaminophenol and phthalic anhydride, is 1: (0.5 to 2), more preferably, 1: (0.8 to 1.2), for example, 1.
According to the invention, when the sample in the coupling reaction stage is used for preparing the medium control solution to be detected, the degree of the coupling reaction can be directly reflected, the feasibility of the esterification reaction in the next stage can be conveniently judged, and when the content of the impurity, namely the diethylaminophenol, in the sample in the coupling reaction stage is measured to be less than or equal to 0.5 percent (HPLC), the coupling reaction is finished.
Wherein, when the middle control solution to be tested is a sample in an esterification reaction stage, a crystallization stage after esterification or a recrystallization stage after esterification, the sample is completely dissolved by using an organic solvent I.
Further, the organic solvent I is preferably selected from any one or more of acetonitrile, N-N-dimethylformamide, methanol and dimethyl sulfoxide, and is more preferably acetonitrile.
According to the invention, the acetonitrile is related to the mobile phase of the sample in the esterification reaction stage, the crystallization stage after esterification or the recrystallization stage after esterification, and does not influence the detection.
Wherein, when preparing the medium control solution to be tested by using the sample in the esterification reaction stage, the method can reflect the degree of the esterification reaction and judge whether the reaction is in a finished state, and when the esterification reaction is carried out until the 4-diethylamino keto acid is less than or equal to 0.5 percent (HPLC), the reaction can be stopped; and when preparing the medium control solution to be tested by using the esterified crystallization stage or esterified recrystallization stage sample, preliminarily judging the quality and purity of the prepared A-Plus finished product.
According to the invention, when the sample to be tested is the finished product of A-Plus to be tested, the finished product of A-Plus is completely dissolved by using an organic solvent II, the concentration of A-Plus in the obtained finished product of A-Plus to be tested is 0.3-1.5 mg/mL, and the selection of the organic solvent II is preferably the same as that of the organic solvent I used in the preparation coupling reaction stage, the esterification reaction stage, the crystallization stage after esterification or the recrystallization stage, such as acetonitrile.
Wherein, when the sample to be detected is the A-plus finished product liquid to be detected, whether the purity and the quality of the prepared A-plus finished product meet the market requirements or not is directly reflected.
According to the invention, the A-Plus standard is dissolved in an organic solvent III, preferably chosen the same as the organic solvent II used for dissolving the finished A-Plus product, for example acetonitrile, to obtain the A-Plus standard solution.
Further, the concentration of the A-Plus standard sample is 1mg/ml.
And 2, injecting the to-be-detected sample solution or the standard sample solution prepared in the step 1 into a high performance liquid chromatograph for chromatographic analysis.
In the step 2, the high performance liquid chromatograph used for chromatographic analysis is an Agilent 1260 high performance liquid chromatograph or instruments with equivalent performance, such as an Agilent 1290 high performance liquid chromatograph, waters H-Class and the like.
The chromatographic column packing is octadecylsilane chemically bonded silica, has a particle size of 2 to 6 μm, preferably 3 to 5 μm, and a column specification of 2.0 to 4.6mm × 150 to 300mm, for example 4.6mm × 250mm.
According to the invention, the chromatographic column is controlled to a temperature of 25 to 35 ℃, for example 30 ℃ during the analysis of the chromatogram; the amount of sample is 1 to 20. Mu.L, preferably 5 to 12. Mu.L, for example 10. Mu.L; the detection wavelength was 225nm.
In the chromatographic analysis, the mobile phase is composed of any one or more of acetonitrile, distilled water, methanol and phosphoric acid, preferably acetonitrile, distilled water and phosphoric acid, for example acetonitrile and 0.1% phosphoric acid.
According to the invention, acetonitrile and 0.1% phosphoric acid constitute a mobile phase, the flow rate is between 0.5 and 5mL/min, preferably between 1 and 2mL/min, and the volume ratio of acetonitrile to 0.1% phosphoric acid is (20-85): (15 to 80).
Further, gradient elution was performed as follows:
in the invention, when the detected center control sample to be detected is a sample in a coupling reaction stage, the center control liquid to be detected prepared in the step 1 is diluted by an organic solvent such as acetonitrile until the peak height of a main peak in liquid chromatography analysis is 1500-2500, otherwise, the main peak is overloaded, and the purity deviation of each substance is large.
Before a sample is detected to obtain an A-Plus finished product, when a central control solution to be detected is prepared by the sample comprising a coupling reaction stage, an esterification reaction stage, crystallization after esterification and a recrystallization stage, the content of impurities in the central control solution to be detected can be comprehensively and accurately reflected, and the degree of reaction progress is detected or an index is provided for the purity or quality of the prepared A-Plus; and when the detected sample is the finished product of the A-Plus to-be-detected liquid, directly reflecting the purity or quality of the prepared A-Plus.
Examples
The present invention is further described below by way of specific examples, which are merely illustrative and do not limit the scope of the present invention in any way.
Example 1
Preparation of central control sample of A-Plus and finished product of A-Plus
Under the protection of nitrogen, adding 165.2g of 3-N, N-diethylamino-m-phenol, 235.8g of toluene and 177.7g of phthalic anhydride into a 1L four-neck flask, then adjusting the reaction temperature to 110-116 ℃, taking a central control sample (marked as a DHBA central control sample) when carrying out heat preservation reaction for 15 hours, and then carrying out crystallization and recrystallization to prepare 4-diethylamino keto acid;
putting 164.88g of the prepared 4-diethylamino keto acid into another 1L four-neck flask, adding 508.68g of n-hexanol and 41.65g of concentrated sulfuric acid, controlling the vacuum degree of a water pump to be-0.086-0.094 MPa, adjusting the temperature of the reaction to be 108-110 ℃, refluxing and dividing water, taking a central control sample (marked as an A-Plus central control sample) when the reaction is carried out for 6h, wherein the 4-diethylamino keto acid is less than or equal to 0.5 percent (HPLC), washing with water, crystallizing and recrystallizing to obtain A-Plus (DHHB), wherein the yield is 92.75 percent, and the HPLC spectrogram is shown in figure 1 and has the purity of 99.69 percent.
Example 2
Analysis of the control test solution
(1) Determination of high performance liquid chromatography conditions
The instrument comprises the following steps: agilent 1260 high performance liquid chromatograph or instrument with equivalent performance
A chromatographic column: type C18 (column packing: octadecylsilane chemically bonded silica), particle size: 5um column specification: 4.6mm X250 mm)
Column temperature: 30 deg.C
Sample introduction amount: 10 μ L
Detection wavelength: 225nm
Flow rate: 1mL/min
Mobile phase elution gradient:
(2) Preparation of central control liquid to be tested
Using dimethyl sulfoxide to prepare a mixture of 1:1 (V: V) dissolving all solids or impurities in the DHBA control sample obtained in example 1, and diluting 1 drop of the sample to 10mL by using acetonitrile to obtain a DHBA control solution to be detected;
and dissolving the A-Plus control sample obtained in the example 1 with acetonitrile, diluting and fixing the volume to obtain the A-Plus control to-be-detected solution.
(3) Chromatography analysis
Injecting the DHBA control solution to be detected into a chromatograph according to the chromatographic conditions, recording a chromatogram, wherein the obtained liquid chromatogram is shown in figure 2, and the figure shows that the DHBA control solution to be detected contains 3-diethylaminophenol with the content of 0.44 percent when the DHBA control solution to be detected is detected at 3.58min, which indicates that the coupling reaction can be finished, wherein the DHBA peak-off time is 18.16min;
similarly, according to the chromatographic conditions, injecting the A-Plus central control solution to be detected into a chromatograph, recording a chromatogram, and obtaining a liquid chromatogram as shown in figure 3, wherein the DHBA content is 0.25%, which indicates that the esterification reaction can be finished, the A-Plus peak time is 27.7min, and the purity reaches 98.3%.
Example 3
Repeatability experiment and analysis of A-Plus finished product to-be-detected liquid
(1) Determination of high performance liquid chromatography conditions
The high performance liquid chromatography conditions in example 3 were the same as those in example 2.
(2) Preparation of A-Plus finished product to-be-tested liquid
50mg of the A-Plus finished product prepared in the example 1 is weighed in a 50mL volumetric flask, and dissolved and diluted with acetonitrile to a constant volume to obtain a 1mg/mL A-Plus finished product solution to be tested.
(3) Chromatography analysis
The A-Plus finished test solutions were subjected to 6 parallel experiments under the above chromatographic conditions, and the peak areas (A1, A2, A3, A4, A5, and A6, respectively) and the Relative Standard Deviation (RSD) results are shown in Table 1.
Table 1:
as can be seen from Table 1, the RSD value of the obtained peak area is less than 2.0% after 6 times of sample introduction, and the high performance liquid chromatography method for detecting the A-Plus finished product has good repeatability.
Example 4
Linear experiment and finished product content determination of A-Plus finished product to-be-detected liquid
(1) Determination of high performance liquid chromatography conditions
The high performance liquid chromatography conditions in example 4 were the same as those in example 2.
(2) Preparation of A-Plus standard solution and A-Plus finished product to-be-detected solution
230mg of A-Plus standard sample (from BASF) is accurately weighed and placed in a 50.0mL clean volumetric flask, dissolved and diluted with acetonitrile to a constant volume, and mixed uniformly to obtain the A-Plus standard solution.
Accurately measuring 1.0mL L, 1.6mL, 2.0mL, 2.4mL and 3.0mL of the A-Plus standard solution into a 10.0mL volumetric flask respectively, diluting with acetonitrile to a constant volume, and uniformly mixing to obtain the A-Plus standard solutions with the concentrations of 60%, 80%, 100%, 120% and 140% of the A-Plus finished product solution to be detected respectively.
50mg of A-Plus finished product prepared in example 1 is weighed and placed in a 50mL volumetric flask, dissolved by acetonitrile, diluted and subjected to volume fixing to obtain the A-Plus finished product solution to be detected with the concentration of 1mg/mL.
(3) Chromatography analysis
Injecting the A-Plus standard solution with the concentration of 60%, 80%, 100%, 120% and 140% equivalent to the concentration of the A-Plus finished product solution to be measured into a chromatograph according to the chromatographic conditions, recording the peak area in the chromatogram, and establishing a standard curve by using the concentration to the peak area; the results are shown in Table 2, and the linear standard curve is shown in FIG. 4.
Table 2:
as can be seen from the combination of Table 2 and FIG. 4, the concentration of the finished product A-Plus obtained in example 1 is proportional to its peak area in the range of 0.4677-1.430 mg/ml, the linear equation is y =24841x +256.37, R =24841x + 2 ＝0.9991。
Injecting the A-Plus finished product to be detected with the concentration of 1mg/mL into a chromatograph according to the chromatographic conditions, recording the peak area in the chromatogram, substituting the peak area into the linear equation in the table 2 for calculation to obtain the measured concentration, wherein the ratio (1 mg/mL) of the measured concentration to the prepared concentration is the content of the A-Plus, and according to the step, carrying out 2 experiments in parallel (respectively recorded as content 1 and content 2), wherein the A-Plus finished product used in the experiment is recorded as batch number 21DHHB002; 2 batches (21 DHHB003 and 21DHHB004, respectively) of finished A-Plus were prepared in the same manner as in example 1, and then prepared into 1mg/mL of finished A-Plus solutions to be tested, and the A-Plus content measurement experiments were conducted 2 times, respectively, in the manner described above, and the results of the three batches are shown in Table 3.
Table 3:
the result shows that the method for measuring the content of the A-plus finished product is stable and reliable.
Example 5
A-Plus finished product accuracy detection
Preparing 3 parts of A-Plus standard solution with the concentration being 80% of that of the finished product of A-Plus to be detected solution in the same way as in example 4, dissolving the finished product of A-Plus prepared in example 1 in acetonitrile, and mixing the prepared 3 parts of A-Plus standard solution with the concentration being 80% of that of the finished product of A-Plus to be detected solution respectively to obtain 3 parts of to-be-detected solution, wherein the 3 parts of to-be-detected solution are respectively marked as 80% -1, 80% -2 and 80% -3; similarly, preparing three parts of 100% solution to be tested, which are respectively represented by 100-1, 100-2 and 100-3; preparing three parts of 120% solution to be tested, which are respectively expressed by 120% -1, 120% -2 and 120% -3.
The background amount, measured amount, added amount and recovery rate in the above 9 samples were measured under the same high performance liquid chromatography conditions as in example 2, and the average value of the recovery rate and the Relative Standard Deviation (RSD) of the recovery rate were calculated accordingly, and the results are shown in table 3:
table 3:
the background amount refers to the weight of the A-Plus finished product prepared in example 1 contained in the liquid to be tested, the measured amount refers to the weight of the A-Plus measured after the A-Plus standard solution is added into the liquid to be tested, and the added amount refers to the weight of the A-Plus in the A-Plus standard solution added into the liquid to be tested.
As can be seen from Table 3, the recovery rate of the A-Plus finished product prepared in example 1 is in the range of 98.0% -102.0%, which indicates that the method is high in accuracy, the reliability of the method is verified, and the RSD between the recovery rates of 9 groups of samples is less than 2.0%, which indicates that the recovery rate experiment is stable and reliable.
Comparative example
Comparative example 1
Determination of A-Plus finished product quality by gas chromatography (GC-MS)
(1) Determination of gas chromatography conditions
Instrument-Agilent 8860 gas chromatograph
Chromatographic column model HP-5 (column specification: 30m 320um 0.25 um)
Column box: initial temperature of 150 deg.C, heating to 300 deg.C at 10 deg.C/min, and maintaining for 13min
A sample inlet: 300 ℃ split ratio: 70:1
A detector: 300 deg.C
Flow rate: 1mL/min
Sample introduction amount: 0.6. Mu.L
Needle washing solvent: acetone.
(2) Preparation of A-Plus finished product to-be-detected liquid
500mg of A-Plus prepared in example 1 was weighed and dissolved in 10mL of acetone to obtain a finished product of A-Plus to be tested.
(3) Chromatography analysis
According to the chromatographic conditions, the A-Plus finished product to-be-tested liquid is injected into a chromatograph for testing, and the results show that: the main peak appearance time is 17.7min, an impurity peak appears at 15.6min, the chromatogram is shown in fig. 5, and after analysis, the molecular weight 295 of the substance at the impurity peak is deduced to be an A-PLUS intramolecular esterification product, and the content of the impurity is found to be unstable during analysis and is deduced to be generated in the GC-MS analysis process.
The invention has been described in detail with reference to the preferred embodiments and illustrative examples. It should be noted, however, that these specific embodiments are merely illustrative of the present invention and do not limit the scope of the present invention in any way. Various modifications, equivalent substitutions and alterations can be made to the technical contents and embodiments of the present invention without departing from the spirit and scope of the present invention, and these are within the scope of the present invention. The scope of the invention is defined by the appended claims.
Claims (10)
1. A method of making a sunscreen a-Plus, comprising: 3-diethylaminophenol and phthalic anhydride are used as raw materials, an intermediate 4-diethylaminoketonic acid is prepared through coupling reaction, the 4-diethylaminoketonic acid is esterified with n-hexanol to obtain an esterification reaction mixture, and the sunscreen agent A-Plus is obtained through water washing, crystallization and recrystallization.
2. The method according to claim 1, wherein the 3-diethylaminophenol and the phthalic anhydride, which are starting materials for the coupling reaction, are used as a reaction solvent in the presence of an aromatic hydrocarbon compound selected from one or more of benzonitrile, toluene, ethylbenzene, o-xylene, m-xylene, p-xylene, and chlorobenzene.
3. The production method according to claim 2, wherein the molar weight ratio of the 3-diethylaminophenol, the phthalic anhydride and the aromatic hydrocarbon compound is 1 (1.01-2): (1.5-5.0).
4. The method according to any one of claims 1 to 3, wherein the purification comprises washing with water, crystallization, and recrystallization.
5. A method for central control and finished product analysis of a sunscreen agent A-Plus, characterized in that the method is used for central control and finished product analysis in the preparation method of A-Plus according to any one of claims 1 to 4, preferably, a sample obtained in one or more stages including a coupling reaction stage, an esterification reaction stage, crystallization after esterification and recrystallization after esterification before the finished product of A-Plus is obtained or the sunscreen agent A-Plus is taken as a sample to be tested, and the degree of reaction progress or the purity of A-Plus is measured.
6. The central control and final product analysis method according to claim 5, wherein the purity determination is performed by high performance liquid chromatography, preferably comprising the steps of:
step 1, respectively preparing a sample solution to be detected and a standard sample solution;
and 2, injecting the to-be-detected sample solution or the standard sample solution prepared in the step 1 into a high performance liquid chromatograph for chromatographic analysis.
7. The central control and finished product analysis method of claim 6, wherein in step 1, the sample solution to be tested is a central control solution to be tested prepared from a sample obtained in one or more stages of a coupling reaction stage, an esterification reaction stage, crystallization after esterification, and recrystallization, or a finished product of A-Plus to be tested prepared from A-Plus finally obtained from a synthesis reaction.
8. The method for analyzing a-Plus central control and a finished product according to claim 7, wherein when the central control solution is prepared from a sample in the coupling reaction stage, the coupling reaction mixture is taken in the reaction stage of 3-diethylaminophenol and phthalic anhydride, dimethyl sulfoxide is added into the coupling reaction mixture, and then the coupling reaction mixture is diluted with an organic solvent such as acetonitrile to a constant volume to obtain the central control solution.
9. The A-Plus central control and product analysis method according to claim 6, wherein in step 2, the HPLC is Agilent 1260 HPLC or equivalent such as Agilent 1290 HPLC, waters H-Class, etc.
10. The A-Plus central control and product analysis method according to claim 6, wherein in the step 2, during the chromatographic analysis, the mobile phase is composed of any one or more of acetonitrile, distilled water, methanol and phosphoric acid, preferably acetonitrile, distilled water and phosphoric acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110939608.0A CN115703715A (en) | 2021-08-16 | 2021-08-16 | Central control and finished product analysis method for sunscreen agent A-Plus |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110939608.0A CN115703715A (en) | 2021-08-16 | 2021-08-16 | Central control and finished product analysis method for sunscreen agent A-Plus |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115703715A true CN115703715A (en) | 2023-02-17 |
Family
ID=85180438
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110939608.0A Pending CN115703715A (en) | 2021-08-16 | 2021-08-16 | Central control and finished product analysis method for sunscreen agent A-Plus |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115703715A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR102633630B1 (en) * | 2023-05-22 | 2024-02-05 | 주식회사 디제이씨 | A preparation method for n-hexyl-2-(4-n,n-diethylamino-2-hydroxybenzoylbenzoate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050165099A1 (en) * | 2002-05-15 | 2005-07-28 | Thomas Heidenfelder | Method for producing 2-(4-n,n-dialkylamino-2-hydroxybenzol)benzoates |
| US20100137629A1 (en) * | 2007-05-02 | 2010-06-03 | Basf Se | Method for the crystallization of 2-(4-n,n-diethyl amino-2-hydroxy benzoyl)-benzoic acid-n-hexyl ester |
| CN112010771A (en) * | 2020-09-08 | 2020-12-01 | 河北建新化工股份有限公司 | Preparation method of n-hexyl 2- (4-diethylamino-2-hydroxybenzoyl) benzoate |
-
2021
- 2021-08-16 CN CN202110939608.0A patent/CN115703715A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050165099A1 (en) * | 2002-05-15 | 2005-07-28 | Thomas Heidenfelder | Method for producing 2-(4-n,n-dialkylamino-2-hydroxybenzol)benzoates |
| US20100137629A1 (en) * | 2007-05-02 | 2010-06-03 | Basf Se | Method for the crystallization of 2-(4-n,n-diethyl amino-2-hydroxy benzoyl)-benzoic acid-n-hexyl ester |
| CN112010771A (en) * | 2020-09-08 | 2020-12-01 | 河北建新化工股份有限公司 | Preparation method of n-hexyl 2- (4-diethylamino-2-hydroxybenzoyl) benzoate |
Non-Patent Citations (2)
| Title |
|---|
| 熊万明等: "《有机化学实验（第2版）》", 北京理工大学出版社, pages: 35 - 36 * |
| 王志鹏等: "防晒类化妆品中二乙氨基羟苯甲酰基苯甲酸己酯的高效液相色谱测定法", 《环境与健康杂志》, vol. 28, no. 2, pages 160 - 162 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR102633630B1 (en) * | 2023-05-22 | 2024-02-05 | 주식회사 디제이씨 | A preparation method for n-hexyl-2-(4-n,n-diethylamino-2-hydroxybenzoylbenzoate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI355490B (en) | Method for analyzing oligomeric proanthocyanidin ( | |
| Zhao et al. | New oxo-bridged calix [2] arene [2] triazine stationary phase for high performance liquid chromatography | |
| Maity et al. | Multispectroscopic analysis and molecular modeling to investigate the binding of beta lactoglobulin with curcumin derivatives | |
| CN115703715A (en) | Central control and finished product analysis method for sunscreen agent A-Plus | |
| Chang et al. | Supramolecular interaction of methotrexate with cucurbit [7] uril and analytical application | |
| Hu et al. | Development of a V-shape bis (tetraoxacalix [2] arene [2] triazine) stationary phase for High performance liquid chromatography | |
| He et al. | Triptycene-based stationary phases for gas chromatographic separations of positional isomers | |
| Kießwetter et al. | 1′, 3′, 3′-Trimethyl-6-nitrospiro [2H-1-benzopyran-2, 2′-indoline]: its thermal enantiomerization and the equilibration with its merocyanine | |
| Dallas et al. | Influence of acetaldehyde, pH, and temperature on transformation of procyanidins in model wine solutions | |
| CN111103375B (en) | Application of chlorogenic acid derivative in medicine quality control | |
| Zang et al. | Hydroxyl and carboxyl group functionalized conjugated microporous nanomaterial as adsorbent for the solid-phase extraction of phenolic endocrine disrupting chemicals from freshwater fish samples | |
| CN101865894B (en) | Method for detecting impurities in freeze-dried powder injection of nedaplatin | |
| CN112094191A (en) | Hydroxytyrosol dihydrocaffeic acid ester with antioxidant activity and synthetic method thereof | |
| CN109251161B (en) | Preparation method of 2-tryptophan bisulfite | |
| Li et al. | Enantiomeric separation of citalopram base by supercritical fluid chromatography | |
| CN114563487A (en) | Method for determining residual solvent in indobufen bulk drug | |
| CN104072491A (en) | Azilsartan derivative compound and preparation method and application thereof | |
| Brinkevich et al. | Radiation-Induced Transformations of Tryptophan and Its Derivatives in Oxygenated Ethanol | |
| Shokova et al. | Homooxacalixarenes: I. Structure, Synthesis, and Chemical Reactions. | |
| EP2754649A1 (en) | Method for determinng impurity concentration in terephthalic acid | |
| Muñoz et al. | Chiroptical studies of flavanone | |
| Lee et al. | High-performance liquid chromatographic method for the determination of Esmolol hydrochloride | |
| Mohammed | Comparative analytical study for determination of acetylsalicylic acid in bulk and in pharmaceutical formulations | |
| CN116754705B (en) | Method for detecting acetic acid and acetate content | |
| CN114957333A (en) | Tenofovir prodrug related substance and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |