CN114149365A - Process control method for synthesizing 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt - Google Patents
Process control method for synthesizing 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt Download PDFInfo
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- -1 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt Chemical compound 0.000 title claims abstract description 46
- 238000000034 method Methods 0.000 title claims abstract description 43
- 238000004886 process control Methods 0.000 title claims abstract description 10
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 6
- OCJKUQIPRNZDTK-UHFFFAOYSA-N ethyl 4,4,4-trifluoro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)C(F)(F)F OCJKUQIPRNZDTK-UHFFFAOYSA-N 0.000 claims abstract description 42
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 239000002994 raw material Substances 0.000 claims abstract description 32
- 238000005481 NMR spectroscopy Methods 0.000 claims abstract description 29
- 238000001228 spectrum Methods 0.000 claims abstract description 28
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims abstract description 24
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 24
- 239000011737 fluorine Substances 0.000 claims abstract description 24
- 239000000126 substance Substances 0.000 claims abstract description 17
- 238000004611 spectroscopical analysis Methods 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims abstract description 3
- 238000005070 sampling Methods 0.000 claims description 18
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 11
- OKKJLVBELUTLKV-MZCSYVLQSA-N deuterated methanol Substances [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-LIDOUZCJSA-N ethanol-d6 Chemical compound [2H]OC([2H])([2H])C([2H])([2H])[2H] LFQSCWFLJHTTHZ-LIDOUZCJSA-N 0.000 claims description 10
- LMRJHNFECNKDKH-UHFFFAOYSA-N 4-(trifluoromethyl)nicotinic acid Chemical compound OC(=O)C1=CN=CC=C1C(F)(F)F LMRJHNFECNKDKH-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical class [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 claims description 8
- MSPCIZMDDUQPGJ-UHFFFAOYSA-N N-methyl-N-(trimethylsilyl)trifluoroacetamide Chemical compound C[Si](C)(C)N(C)C(=O)C(F)(F)F MSPCIZMDDUQPGJ-UHFFFAOYSA-N 0.000 claims description 8
- UHOVQNZJYSORNB-MZWXYZOWSA-N benzene-d6 Chemical compound [2H]C1=C([2H])C([2H])=C([2H])C([2H])=C1[2H] UHOVQNZJYSORNB-MZWXYZOWSA-N 0.000 claims description 6
- 229960003405 ciprofloxacin Drugs 0.000 claims description 6
- YMWUJEATGCHHMB-DICFDUPASA-N dichloromethane-d2 Chemical compound [2H]C([2H])(Cl)Cl YMWUJEATGCHHMB-DICFDUPASA-N 0.000 claims description 6
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 4
- 150000007960 acetonitrile Chemical class 0.000 claims description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical class CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 3
- CSCPPACGZOOCGX-WFGJKAKNSA-N deuterated acetone Substances [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 claims description 3
- JUJWROOIHBZHMG-RALIUCGRSA-N pyridine-d5 Chemical compound [2H]C1=NC([2H])=C([2H])C([2H])=C1[2H] JUJWROOIHBZHMG-RALIUCGRSA-N 0.000 claims description 3
- 150000003613 toluenes Chemical class 0.000 claims description 3
- WRXXBTBGBXYHSG-UHFFFAOYSA-N 2,6-dichloro-4-(trifluoromethyl)pyridine-3-carbonitrile Chemical compound FC(F)(F)C1=CC(Cl)=NC(Cl)=C1C#N WRXXBTBGBXYHSG-UHFFFAOYSA-N 0.000 claims description 2
- GEHMLBFNZKJDQM-UHFFFAOYSA-N 2-chloro-4-(trifluoromethyl)benzonitrile Chemical compound FC(F)(F)C1=CC=C(C#N)C(Cl)=C1 GEHMLBFNZKJDQM-UHFFFAOYSA-N 0.000 claims description 2
- 238000012545 processing Methods 0.000 claims description 2
- 238000010966 qNMR Methods 0.000 claims 1
- 230000003595 spectral effect Effects 0.000 claims 1
- 238000004458 analytical method Methods 0.000 abstract description 7
- DGJMPUGMZIKDRO-UHFFFAOYSA-N cyanoacetamide Chemical compound NC(=O)CC#N DGJMPUGMZIKDRO-UHFFFAOYSA-N 0.000 abstract description 7
- 125000001153 fluoro group Chemical group F* 0.000 abstract description 3
- JRLZWXISQMMITA-UHFFFAOYSA-N 2-hydroxy-6-oxo-4-(trifluoromethyl)-1h-pyridine-3-carbonitrile Chemical compound OC=1NC(=O)C=C(C(F)(F)F)C=1C#N JRLZWXISQMMITA-UHFFFAOYSA-N 0.000 abstract 1
- 238000006073 displacement reaction Methods 0.000 abstract 1
- 235000019000 fluorine Nutrition 0.000 description 20
- 238000004364 calculation method Methods 0.000 description 9
- 239000012295 chemical reaction liquid Substances 0.000 description 9
- 238000001514 detection method Methods 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- RLQJEEJISHYWON-UHFFFAOYSA-N flonicamid Chemical compound FC(F)(F)C1=CC=NC=C1C(=O)NCC#N RLQJEEJISHYWON-UHFFFAOYSA-N 0.000 description 4
- 238000004817 gas chromatography Methods 0.000 description 4
- 230000005311 nuclear magnetism Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 239000005900 Flonicamid Substances 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000004812 organic fluorine compounds Chemical class 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—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 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N24/00—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects
- G01N24/08—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects by using nuclear magnetic resonance
- G01N24/088—Assessment or manipulation of a chemical or biochemical reaction, e.g. verification whether a chemical reaction occurred or whether a ligand binds to a receptor in drug screening or assessing reaction kinetics
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Abstract
The invention belongs to the field of magnetic resonance analysis, and particularly relates to a method for determining the conversion rate of raw materials and the content of a product in the process control of the reaction of ethyl trifluoroacetoacetate and cyanoacetamide to generate 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt by quantitative nuclear magnetic resonance fluorine spectrometry. The method comprises the steps of respectively collecting nuclear magnetic resonance fluorine spectra of key raw materials and products, obtaining peak areas of all fluorine parts by estimating fluorine chemical displacement of each component and integrating, and then calculating to obtain the content of 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt and the content and the conversion rate of ethyl trifluoroacetoacetate. The method is simple and convenient to operate, can quickly and accurately realize the process control of synthesizing the 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine, and provides a powerful support for the preparation of a target product.
Description
Technical Field
The invention belongs to the field of magnetic resonance analysis, and particularly relates to a process control method for synthesizing 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt, which adopts a quantitative nuclear magnetic resonance fluorine spectrometry to simultaneously realize the determination of the conversion rate of raw materials and the content of the raw materials and products.
Background
Flonicamid, also known as N-cyanomethyl-4- (trifluoromethyl) nicotinamide, is a novel selective low-toxicity pyridylamide pesticide, and has the characteristics of high efficiency, strong toxicity, small dosage, rain resistance and no pollution to the environment, so that the flonicamid is a key object for pesticide research.
3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt is an important intermediate in the synthesis process of flonicamid, and is mainly synthesized from ethyl trifluoroacetoacetate and cyanoacetamide, as shown in the following equation. The conversion rate of the ethyl trifluoroacetoacetate in the reaction process can visually indicate the completion degree of the reaction, the yield of the reaction can be evaluated by the content of the 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt, and if the conversion rate of the raw materials and the content of the product can be detected at the same time, the method has important significance for reaction control and product quality control. Therefore, a method for simultaneously analyzing the raw material of ethyl trifluoroacetoacetate and the product of 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt is needed.
Patent CN111458432A discloses a method for detecting ethyl trifluoroacetoacetate by high performance liquid chromatography. The method is reduced in a laboratory, and the difference of the molar absorption coefficients of the raw materials of the ethyl trifluoroacetoacetate and the 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt is large, and the peak areas of the ethyl trifluoroacetoacetate and the 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt are nearly 100 times different under the same concentration, so that the raw materials and the product cannot be simultaneously monitored by an area normalization method; if the quantitative analysis method in the patent is adopted, the raw materials and the products are respectively quantitatively determined, the experimental period is long, and the process is complicated.
In the literature, "synthesis of ethyl trifluoroacetoacetate" the area normalized content is measured by gas chromatography, but the 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt synthesized from ethyl trifluoroacetoacetate and cyanoacetamide has a high boiling point and cannot be gasified at a gas injection port, so that the gas chromatography is not suitable for process control and monitoring of the reaction.
The quantitative nuclear magnetic resonance technology is a mature instrument analysis method, the basic principle is that the area of a resonance peak in NMR is in direct proportion to the number of atoms contained in the resonance peak, and the method has the advantages of no dependence on a high-purity standard product of a measured object, no need of introducing any correction factor, high speed, simplicity and accuracy. The nuclear magnetic resonance fluorine spectrum method is widely applied to qualitative analysis of organic fluorine compounds due to the characteristics of similar magnetic rotation ratio to 1H, wide spectrum peak range, difficult peak overlapping of similar structures and the like. At present, no related report of quantitative nuclear magnetic fluorine spectrum for detecting the conversion rate and content in the process control of generating 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt by reacting ethyl trifluoroacetoacetate with cyanoacetamide is available.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a method for determining the conversion rate of raw materials and the content of products in the process of generating 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt by reacting ethyl trifluoroacetoacetate with cyanoacetamide through quantitative nuclear magnetic resonance fluorine spectrum.
The technical scheme for solving the technical problems is as follows:
the invention provides a process control method for synthesizing 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt, which is characterized in that a quantitative nuclear magnetic resonance fluorine spectrometry method is adopted to simultaneously determine the conversion rate of raw materials, the content of the raw materials and the content of products; wherein the raw material is ethyl trifluoroacetoacetate;
further, the quantitative nuclear magnetic resonance fluorine spectrometry comprises the following steps:
(1) solution preparation: dissolving 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt reaction liquid and an internal standard substance in a deuterated reagent, transferring the deuterated reagent to a nuclear magnetic tube, and using the nuclear magnetic tube for nuclear magnetic fluorine spectrum determination;
(2) setting nuclear magnetic resonance instrument parameters: the method comprises the steps of sampling spectrum width, sampling center frequency, sampling point number, temperature, delay time, pulse angle and sampling times;
(3) and (4) processing a result: after the determination is finished, determining characteristic peaks of the raw material, the product and the internal standard substance, calculating peak areas, and calculating to obtain the conversion rate of the raw material, the content of the raw material and the content of the product;
wherein, the calculation formula (a) of the content of the raw materials and the product is as follows:
x1-is the percentage content, expressed in%, of 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt (product) or ethyl trifluoroacetoacetate (raw material) in the sample to be tested;
AA-peak area of characteristic signal peak for 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt (product) or ethyl trifluoroacetoacetate (raw material);
AB-peak area of the characteristic signal peak of the internal standard;
NA-the number of fluorine atoms being 1mol of 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt (product) or ethyl trifluoroacetoacetate (starting material);
NB-the number of fluorines contained in the quantification peak for 1mol of internal standard;
MA-is the relative molecular mass of 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt (product) or ethyl trifluoroacetoacetate (raw material);
MB-relative molecular mass as internal standard;
mA-is the mass of the reaction solution sample containing 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt (product) and ethyl trifluoroacetoacetate (raw material) and ethyl trifluoroacetoacetate;
mB-is the mass of the weighed internal standard;
PB-purity of the internal standard, expressed in%;
wherein, the calculation formula of the conversion rate of the trifluoroacetyl ethyl acetate is as follows:
x2-is the percentage of ethyl trifluoroacetoacetate conversion, expressed as%;
SA-is the mole number of the ethyl trifluoroacetoacetate feeding amount;
SB-to calculate the moles of ethyl trifluoroacetoacetate remaining;
further, the internal standard substance is one or more of 2-chloro-4-trifluoromethylbenzonitrile, N-methyl-N- (trimethylsilyl) trifluoroacetamide, trifluorotoluene, ciprofloxacin, 4-trifluoromethylnicotinic acid or 2, 6-dichloro-3-cyano-4-trifluoromethylpyridine;
preferably, the internal standard is 4-trifluoromethylnicotinic acid, N-methyl-N- (trimethylsilyl) trifluoroacetamide or ciprofloxacin;
further, the dosage of the 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt reaction solution is 100-500 mg; the dosage of the internal standard substance is 10-40 mg; the dosage of the deuterated reagent is 0.3-0.8 mL; the range not only ensures that the nuclear magnetic resonance apparatus can accurately detect the resonance signal, but also can reduce the interference of the calculation peak, thereby improving the accuracy of the detection result;
further, the deuterated reagent is one or more of deuterated ethanol, deuterated dimethyl sulfoxide, deuterated methanol, deuterated acetonitrile, deuterated acetone, deuterated pyridine, deuterated benzene, deuterated toluene or deuterated dichloromethane;
preferably, the deuterated reagent is deuterated methanol or deuterated dimethyl sulfoxide;
furthermore, the sampling spectrum width is 237.16ppm, the sampling center frequency is-100.00 ppm, and the number of sampling points is 64K;
further, the temperature is 25-35 ℃, the delay time is 5-40 s, the pulse angle is 45-120 degrees, and the sampling frequency is 16-128 times;
preferably, the temperature is 30 ℃, the delay time is 20 s-40 s, the pulse angle is 90 degrees, and the sampling times are 32 times.
The Chinese naming of the compound of the invention conflicts with the structural formula, and the structural formula is taken as the standard; except for obvious errors in the formula.
The invention has the beneficial effects that:
the method firstly uses a quantitative nuclear magnetic resonance fluorine spectrum method to measure the conversion rate of raw materials, the content of raw materials and the content of products in the process control of the reaction of the ethyl trifluoroacetoacetate and the cyanoacetamide to generate the 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt. The problems that the area normalization value is inaccurate and the boiling point of a gas chromatography product is high and the gas chromatography product cannot be gasified due to different molar absorption coefficients of raw materials and the product in the current high performance liquid chromatography analysis process are solved;
compared with the quantitative nuclear magnetic resonance hydrogen spectrum, the quantitative nuclear magnetic resonance fluorine spectrum measuring method developed by the invention has the advantages that the structural similarity is not easy to generate peak overlapping, the interference of the peaks is reduced, and the accuracy of the detection result is improved;
the method can quickly and accurately evaluate the conversion rate of the raw materials, the content of the raw materials and the content of the product in the process of generating the 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt by reacting the ethyl trifluoroacetoacetate with the cyanoacetamide, and provides a strong evidence for synthesis.
Drawings
FIG. 1: nuclear magnetic resonance fluorine spectrum in example 1;
FIG. 2: nuclear magnetic resonance fluorine spectrum in example 2;
FIG. 3: nuclear magnetic resonance fluorine spectrum in example 3;
FIG. 4: nuclear magnetic resonance fluorine spectrum in comparative example 1;
FIG. 5: nuclear magnetic resonance fluorine spectrum in comparative example 2.
Detailed Description
The invention is illustrated but not limited by the following examples. The technical solutions protected by the present invention are all the simple replacements or modifications made by the skilled person in the art.
Example 1:
according to the existing reaction liquid sample of 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt which reacts for 4 hours, the conversion rate of ethyl trifluoroacetoacetate is estimated to be 50% by a synthesizer according to the synthesis process, an accurate reaction process needs to be known, and a nuclear magnetic resonance fluorine spectrum method is adopted for detection and analysis, and the specific steps comprise:
(1) accurately weighing 35.79mg of internal standard 4-trifluoromethyl nicotinic acid with the content of 98.24% and 267.8mg of reaction liquid of 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt into a sample bottle, adding 0.4mL of deuterated dimethyl sulfoxide to dissolve, transferring to a nuclear magnetic tube, and carrying out nuclear magnetic resonance detection. The sampling center frequency is-100 ppm, the pulse flip angle is 90 degrees, the test temperature is 30 ℃, the spectrum width is 237.16ppm, the delay time is 20s, the scanning times are 32 times, and the number of sampling points is 64K.
(2) As shown in fig. 1, in the fluorine spectrum, a quantitative peak of 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt at δ of 64.79ppm was obtained; chemical shifts are quantitative peaks for ethyl trifluoroacetoacetate at δ 81.90 and 84.25 ppm; the chemical shift is a quantitative peak of 4-trifluoromethyl nicotinic acid at the position of delta-60.84 ppm; the signal peaks are well separated and symmetrical and uniform, and meet the requirement of quantitative nuclear magnetism. The content of 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt was 12.72%, the content of ethyl trifluoroacetoacetate was 11.42%, and the conversion of ethyl trifluoroacetoacetate was 51.94% according to the calculation of the content calculation formula (a). Repeat 6 times, standard deviation 0.29%, relative standard deviation 0.21%.
Example 2:
according to the existing reaction liquid sample of the 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt which reacts for 16 hours, the conversion rate of ethyl trifluoroacetoacetate is estimated to be about 80% by a synthesizer according to the synthesis process, the accurate reaction process needs to be known, and nuclear magnetic resonance is adopted for detection and analysis, and the specific steps comprise:
(1) the method comprises the steps of accurately weighing 25.78mg of internal standard N-methyl-N- (trimethylsilyl) trifluoroacetamide and 310.2mg of reaction liquid of 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt with the content of 97.50 percent into a sample bottle, adding 0.4mL of deuterated methanol to dissolve the internal standard N-methyl-N- (trimethylsilyl) trifluoroacetamide and then transferring the internal standard N-methyl-N- (trimethylsilyl) trifluoroacetamide and the reaction liquid to a nuclear magnetic tube for nuclear magnetic resonance detection. The sampling center frequency is-100 ppm, the pulse flip angle is 90 degrees, the test temperature is 30 ℃, the spectrum width is 237.16ppm, the delay time is 20s, the scanning times are 32 times, and the number of sampling points is 64K.
(2) As shown in fig. 2, in the fluorine spectrum, a quantitative peak of 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt was present at δ of 66.83 ppm; chemical shift is quantitative peak of ethyl trifluoroacetoacetate at delta-83.73 ppm; chemical shifts are quantified peaks for N-methyl-N- (trimethylsilyl) trifluoroacetamide as an internal standard at δ 77.32 ppm; the signal peaks are well separated and symmetrical and uniform, and meet the requirement of quantitative nuclear magnetism. According to the calculation of the content formula (a), the content of 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt is 27.03%, the content of ethyl trifluoroacetoacetate is 2.62%, and the conversion rate of ethyl trifluoroacetoacetate is 88.98%. Repeat 6 times, standard deviation 0.16%, relative standard deviation 0.19%.
Example 3:
in the existing reaction liquid sample of the 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt which reacts for 24 hours, a synthesizer needs to know the accurate reaction process, and nuclear magnetic resonance is adopted for detection and analysis, and the specific steps comprise:
(1) 13.10mg of ciprofloxacin as an internal standard with the content of 98.10% and 315.20mg of reaction liquid of 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt are accurately weighed into a sample bottle, 0.4mL of deuterated dimethyl sulfoxide is added to be dissolved, and then the dissolved solution is transferred to a nuclear magnetic tube for nuclear magnetic resonance detection. The sampling center frequency is-100 ppm, the pulse flip angle is 90 degrees, the test temperature is 30 ℃, the spectrum width is 237.16ppm, the delay time is 20s, the scanning times are 32 times, and the number of sampling points is 64K.
(2) As shown in fig. 3, in the fluorine spectrum, a quantitative peak of 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt was present at δ of 64.59 ppm; chemical shift is quantitative peak of ethyl trifluoroacetoacetate at delta 84.01 ppm; chemical shift is quantitative peak of ciprofloxacin as internal standard at delta-121.90 ppm; the signal peaks are well separated and symmetrical and uniform, and meet the requirement of quantitative nuclear magnetism. According to the content calculation formula (a), the content of 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt is 34.59%, the content of ethyl trifluoroacetoacetate is 1.04%, and the conversion rate of the ethyl trifluoroacetoacetate is as follows: 95.62 percent. Repeat 6 times, standard deviation 0.25%, relative standard deviation 0.23%.
Comparative example 1:
preparing a reaction liquid sample of 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt with known content, and detecting and analyzing by adopting nuclear magnetic resonance, wherein the method comprises the following specific steps:
(1) 28.96mg of internal standard 4-trifluoromethyl nicotinic acid with the content of 98.24%, 40.25mg of 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt with the content of 98.00% and 38.02mg of ethyl trifluoroacetoacetate with the content of 97.65% are accurately weighed into a sample bottle, the known total sample mass is 78.27mg, wherein the proportion of 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt is 50.40%, the proportion of ethyl trifluoroacetoacetate is 47.43%, 0.4mL of deuterated dimethyl sulfoxide is added for dissolution, and then the mixture is transferred to a nuclear magnetic tube for nuclear magnetic resonance detection. The sampling center frequency is-100 ppm, the pulse flip angle is 60 degrees, the test temperature is 30 ℃, the spectrum width is 237.16ppm, the delay time is 10s, the scanning times are 16 times, and the number of sampling points is 32K.
(2) As shown in fig. 4, in the fluorine spectrum, a quantitative peak of 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt was present at δ of 64.79 ppm; chemical shifts are quantitative peaks for ethyl trifluoroacetoacetate at δ 81.90 and 84.25 ppm; the chemical shift is a quantitative peak of 4-trifluoromethyl nicotinic acid at the position of delta-60.84 ppm; the signal peaks are well separated and symmetrical and uniform, and meet the requirement of quantitative nuclear magnetism. The actual measurement content of the 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt is 39.29% and the actual measurement content of the ethyl trifluoroacetoacetate is 38.64% according to the calculation of the content calculation formula (a). The recovery rate of the 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt is 77.97 percent, the recovery rate of the ethyl trifluoroacetoacetate is 81.45 percent, and the accuracy is poor after the reaction is repeated for 6 times.
Comparative example 2:
experiments prove that besides the deuterated dimethyl sulfoxide and the deuterated methanol, the deuterated ethanol is also a good solvent, but because the deuterated ethanol is expensive, the deuterated ethanol is not selected in consideration of cost. The rest deuterated reagents are deuterated acetonitrile, deuterated acetone, deuterated pyridine, deuterated benzene, deuterated toluene or deuterated dichloromethane, which have different degrees of splitting and cannot meet the quantitative requirement, and 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt and ethyl trifluoroacetoacetate have different degrees of splitting in the deuterated acetonitrile solvent shown in figure 5, so that accurate quantitative results are difficult to obtain through integration.
TABLE 1 parameters of deuterated reagents and internal standard substances used in the examples and comparative examples
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the inventive concept of the present invention, and these changes and modifications are all within the scope of the present invention.
Claims (10)
1. A process control method for synthesizing 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt is characterized in that a quantitative nuclear magnetic resonance fluorine spectrum method is adopted to simultaneously determine the conversion rate of raw materials, the content of the raw materials and the content of products; wherein the raw material is ethyl trifluoroacetoacetate.
2. The method of claim 1, wherein the quantitative nmr spectroscopy comprises the steps of:
(1) solution preparation: dissolving the 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt reaction solution and the internal standard substance in a deuterated reagent, and transferring the solution to a nuclear magnetic tube for nuclear magnetic fluorine spectrum determination;
(2) setting nuclear magnetic resonance instrument parameters: the method comprises the steps of sampling spectrum width, sampling center frequency, sampling point number, temperature, delay time, pulse angle and sampling times;
(3) and (4) processing a result: and after the determination is finished, determining characteristic peaks of the raw material, the product and the internal standard substance, calculating peak areas, and calculating to obtain the conversion rate of the raw material, the content of the raw material and the content of the product.
3. The method according to claim 2, wherein the internal standard is one or more of 2-chloro-4-trifluoromethylbenzonitrile, N-methyl-N- (trimethylsilyl) trifluoroacetamide, trifluorotoluene, ciprofloxacin, 4-trifluoromethylnicotinic acid, or 2, 6-dichloro-3-cyano-4-trifluoromethylpyridine.
4. The method of claim 3, wherein the internal standard is 4-trifluoromethylnicotinic acid, N-methyl-N- (trimethylsilyl) trifluoroacetamide, or ciprofloxacin.
5. The method according to claim 2, wherein the amount of the 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt reaction solution is 100-500 mg; the dosage of the internal standard substance is 10-40 mg; the dosage of the deuterated reagent is 0.3-0.8 mL.
6. The method of claim 2, wherein the deuterated reagent is one or more of deuterated ethanol, deuterated dimethyl sulfoxide, deuterated methanol, deuterated acetonitrile, deuterated acetone, deuterated pyridine, deuterated benzene, deuterated toluene or deuterated dichloromethane.
7. The method of claim 6, wherein the deuterated reagent is deuterated methanol or deuterated dimethyl sulfoxide.
8. The method of claim 2, wherein the sampling spectral width is 237.16ppm, the sampling center frequency is-100.00 ppm, and the number of sampling points is 64K.
9. The method according to claim 2, wherein the temperature is 25-35 ℃, the delay time is 5-40 s, the pulse angle is 45-120 °, and the sampling times are 16-128.
10. The method according to claim 9, wherein the temperature is 30 ℃, the delay time is 20s to 40s, the pulse angle is 90 °, and the number of sampling times is 32.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101851193A (en) * | 2009-10-20 | 2010-10-06 | 西华大学 | Preparation method of 4-trifluoromethyl nicotinic acid |
| CN103626697A (en) * | 2013-12-05 | 2014-03-12 | 贵州威顿晶磷电子材料有限公司 | Preparation method for 2-chlorine-4-trifluoromethyl-3-cyanopyridine |
| CN108191749A (en) * | 2018-03-29 | 2018-06-22 | 上海赫腾精细化工有限公司 | A kind of preparation method of flonicamid and its intermediate 4- trifluoromethyl nicotinic acids |
| CN111458432A (en) * | 2020-04-15 | 2020-07-28 | 京博农化科技有限公司 | Method for detecting ethyl trifluoroacetoacetate through high performance liquid chromatography |
| CN112557432A (en) * | 2020-11-20 | 2021-03-26 | 江苏中旗科技股份有限公司 | Content determination method of bis- (N-bis (dimethylamino) methylene) -chloridized imine salt catalyst |
-
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101851193A (en) * | 2009-10-20 | 2010-10-06 | 西华大学 | Preparation method of 4-trifluoromethyl nicotinic acid |
| CN103626697A (en) * | 2013-12-05 | 2014-03-12 | 贵州威顿晶磷电子材料有限公司 | Preparation method for 2-chlorine-4-trifluoromethyl-3-cyanopyridine |
| CN108191749A (en) * | 2018-03-29 | 2018-06-22 | 上海赫腾精细化工有限公司 | A kind of preparation method of flonicamid and its intermediate 4- trifluoromethyl nicotinic acids |
| CN111458432A (en) * | 2020-04-15 | 2020-07-28 | 京博农化科技有限公司 | Method for detecting ethyl trifluoroacetoacetate through high performance liquid chromatography |
| CN112557432A (en) * | 2020-11-20 | 2021-03-26 | 江苏中旗科技股份有限公司 | Content determination method of bis- (N-bis (dimethylamino) methylene) -chloridized imine salt catalyst |
Non-Patent Citations (1)
| Title |
|---|
| 李杰 等: "3-氨甲基-4-三氟甲基吡啶的合成研究", 《有机化学》, vol. 28, no. 9, pages 1637 - 1640 * |
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