CN114149365B - Process control method for synthesizing 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt - Google Patents
Process control method for synthesizing 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt Download PDFInfo
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- CN114149365B CN114149365B CN202111498928.3A CN202111498928A CN114149365B CN 114149365 B CN114149365 B CN 114149365B CN 202111498928 A CN202111498928 A CN 202111498928A CN 114149365 B CN114149365 B CN 114149365B
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- -1 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt Chemical compound 0.000 title claims abstract description 44
- 238000000034 method Methods 0.000 title claims abstract description 29
- 238000004886 process control Methods 0.000 title claims abstract description 8
- 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 43
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 238000005481 NMR spectroscopy Methods 0.000 claims abstract description 34
- 239000002994 raw material Substances 0.000 claims abstract description 30
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims abstract description 26
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 26
- 239000011737 fluorine Substances 0.000 claims abstract description 26
- 238000001228 spectrum Methods 0.000 claims abstract description 25
- 239000000126 substance Substances 0.000 claims abstract description 21
- 238000005070 sampling Methods 0.000 claims description 17
- 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
- OKKJLVBELUTLKV-MZCSYVLQSA-N deuterated methanol Substances [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- 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
- LFQSCWFLJHTTHZ-LIDOUZCJSA-N ethanol-d6 Chemical compound [2H]OC([2H])([2H])C([2H])([2H])[2H] LFQSCWFLJHTTHZ-LIDOUZCJSA-N 0.000 claims description 8
- 238000004611 spectroscopical analysis Methods 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 6
- 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
- 239000012295 chemical reaction liquid Substances 0.000 claims description 6
- 229960003405 ciprofloxacin Drugs 0.000 claims description 6
- 150000007960 acetonitrile Chemical class 0.000 claims description 4
- YMWUJEATGCHHMB-DICFDUPASA-N dichloromethane-d2 Chemical compound [2H]C([2H])(Cl)Cl YMWUJEATGCHHMB-DICFDUPASA-N 0.000 claims description 4
- 238000005259 measurement Methods 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
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 2
- 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
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 238000004458 analytical method Methods 0.000 abstract description 8
- DGJMPUGMZIKDRO-UHFFFAOYSA-N cyanoacetamide Chemical compound NC(=O)CC#N DGJMPUGMZIKDRO-UHFFFAOYSA-N 0.000 abstract description 7
- 230000010354 integration Effects 0.000 abstract description 2
- 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
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 abstract 1
- 238000006073 displacement reaction Methods 0.000 abstract 1
- 238000004364 calculation method Methods 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 230000005311 nuclear magnetism Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 3
- RLQJEEJISHYWON-UHFFFAOYSA-N flonicamid Chemical compound FC(F)(F)C1=CC=NC=C1C(=O)NCC#N RLQJEEJISHYWON-UHFFFAOYSA-N 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 239000005900 Flonicamid Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000005336 cracking Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 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
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical class ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 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
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000002309 gasification Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000004812 organic fluorine compounds Chemical class 0.000 description 1
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
-
- 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
Abstract
The invention belongs to the field of magnetic resonance analysis, and particularly relates to a method for controlling raw material conversion rate and product content in the process of quantitatively measuring ethyl trifluoroacetoacetate and cyanoacetamide to react to generate 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt by using nuclear magnetic resonance fluorine spectrum. The method is characterized in that nuclear magnetic resonance fluorine spectrums of key raw materials and products are respectively collected, the fluoride chemical displacement of each component is estimated, the peak area of each part of fluorine is obtained through integration, and the content of 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt, the content of ethyl trifluoroacetoacetate and the conversion rate are calculated. The method of the invention has simple operation, can rapidly and accurately realize the process control of synthesizing the 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine, and provides powerful support for the preparation of target products.
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-trifluoromethyl pyridine triethylamine salt, which adopts a quantitative nuclear magnetic resonance fluorine spectrometry to simultaneously measure the conversion rate of raw materials, the content of raw materials and the content of products.
Background
The flonicamid, also called N-cyanomethyl-4- (trifluoromethyl) nicotinamide, is a novel selective low-toxicity pyridine amide pesticide, has the characteristics of high efficiency, strong toxicity, small dosage, rain resistance and no pollution to the environment, and is a key object of pesticide research.
The 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt is an important intermediate in the synthesis process of flonicamid, and is mainly synthesized by ethyl trifluoroacetoacetate and cyanoacetamide, and the following equation is shown. The conversion rate of the ethyl trifluoroacetoacetate in the reaction process can intuitively represent the completion of the reaction, the content of the 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt can evaluate the yield of the reaction, and if the conversion rate of raw materials and the content of products can be detected at the same time, the method has important significance for reaction control and product quality control. There is therefore a need for a method for simultaneous analysis of the starting ethyl trifluoroacetoacetate and the product 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt.
Patent CN111458432a discloses a method for detecting ethyl trifluoroacetoacetate by high performance liquid chromatography. The method is reduced in a laboratory, and the fact that the molar absorptivity of the raw materials of ethyl trifluoroacetoacetate and 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt are relatively large in difference, and the peak areas of the raw materials and the products are approximately 100 times different under the same concentration is found, so that the raw materials and the products cannot be monitored simultaneously by an area normalization method; if the quantitative analysis method in the patent is adopted, the quantitative determination is respectively carried out on the raw materials and the products, the experimental period is long, and the process is complicated.
In the literature of synthesis of ethyl trifluoroacetoacetate, the content of the ethyl trifluoroacetoacetate is measured by using a gas chromatography, but the 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt synthesized by using ethyl trifluoroacetoacetate and cyanoacetamide has a higher boiling point and cannot be gasified at a gas phase inlet, so that the gas chromatography is not suitable for process control monitoring of the reaction.
The quantitative nuclear magnetic resonance technology is a mature instrument analysis method, and the basic principle is that the resonance peak area 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 substance of an object to be detected, no need of introducing any correction factor, high speed, simplicity and accuracy. The nuclear magnetic resonance fluorine spectrometry 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 occurrence of peak overlapping of structural analogues and the like. At present, no relevant report exists on the conversion rate and content in the process control of detecting the reaction of ethyl trifluoroacetoacetate and cyanoacetamide to generate 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt by quantitative nuclear magnetic resonance spectroscopy.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a method for controlling the conversion rate of raw materials and the content of products in the process of quantitatively measuring the reaction of ethyl trifluoroacetoacetate and cyanoacetamide to generate 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt by 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-trifluoromethyl pyridine triethylamine salt, which is characterized in that quantitative nuclear magnetic resonance fluorine spectrometry is adopted to simultaneously determine the conversion rate of raw materials, the content of 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) Preparing a solution: dissolving 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt reaction liquid and an internal standard substance in a deuteration reagent, and transferring to a nuclear magnetic tube for nuclear magnetic fluorine spectrum determination;
(2) Setting nuclear magnetic resonance 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 (3) result processing: after the measurement is finished, determining characteristic peaks of the raw materials, the products and the internal standard substances, calculating peak areas, and calculating to obtain the conversion rate of the raw materials, the contents of the raw materials and the products;
wherein, the calculation formula (a) of the contents of the raw materials and the products is as follows:
x 1 -as percentage of 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt (product) or ethyl trifluoroacetoacetate (raw material) in the sample to be testedContent in%;
A A peak areas of characteristic signal peaks for 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt (product) or ethyl trifluoroacetoacetate (starting material);
A B -peak areas that are characteristic signal peaks of the internal standard;
N A -number of fluorine of 1mol of 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt (product) or ethyl trifluoroacetoacetate (starting material);
N B -quantifying the number of fluorine contained in the peak for 1mol of internal standard;
M A -relative molecular mass of 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt (product) or ethyl trifluoroacetoacetate (starting material);
M B -the relative molecular mass of the internal standard;
m A -the mass of the weighed sample containing 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt (product) and ethyl trifluoroacetoacetate (raw material) and ethyl trifluoroacetoacetate reaction solution;
m B -the mass of the internal standard being weighed;
P B -purity of the internal standard in%;
wherein, the calculation formula of the conversion rate of the ethyl trifluoroacetoacetate is as follows:
x 2 -ethyl trifluoroacetoacetate conversion in percent;
S A -moles of ethyl trifluoroacetoacetate charge;
S B -the number of moles of ethyl trifluoroacetoacetate remaining for the calculation;
further, the internal standard is one or more of 2-chloro-4-trifluoromethyl benzonitrile, N-methyl-N- (trimethylsilyl) trifluoroacetamide, benzotrifluoride, ciprofloxacin, 4-trifluoromethyl nicotinic acid or 2, 6-dichloro-3-cyano-4-trifluoromethyl pyridine;
preferably, the internal standard is 4-trifluoromethyl nicotinic acid, N-methyl-N- (trimethylsilyl) trifluoroacetamide or ciprofloxacin;
further, the dosage of the 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt reaction solution is 100-500 mg; the dosage of the internal standard substance is 10-40 mg; the dosage of the deuteration reagent is 0.3-0.8 mL; the range ensures that the nuclear magnetic resonance instrument can accurately detect resonance signals and reduce the interference of calculation peaks, thereby improving the accuracy of detection results;
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;
further, the sampling spectrum width is 237.16ppm, the sampling center frequency is-100.00 ppm, and the sampling point number 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 times are 16-128 times;
preferably, the temperature is 30 ℃, the delay time is 20-40 s, the pulse angle is 90 degrees, and the sampling times are 32 times.
The Chinese naming of the compound in the invention conflicts with the structural formula, and the structural formula is taken as the reference; except for obvious structural errors.
The invention has the beneficial effects that:
according to the invention, the quantitative nuclear magnetic resonance fluorine spectrometry is used for measuring the raw material conversion rate, the raw material and the product content in the process of reacting ethyl trifluoroacetoacetate with cyanoacetamide to generate 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt for the first time. Solves the problems of inaccurate area normalization value and higher boiling point of gas chromatographic products and incapability of gasification caused by different molar absorptivity of raw materials and products in the current high performance liquid chromatographic analysis process;
compared with a 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 analogues are not easy to have peak overlapping, the interference of the peaks is reduced, and the accuracy of the detection result is improved;
the invention can rapidly and accurately evaluate the raw material conversion rate, raw material and product content in the process of generating 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt by the reaction of the ethyl trifluoroacetoacetate and the cyanoacetamide, and provides 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. Simple alternatives and modifications of the invention will be apparent to those skilled in the art and are within the scope of the invention as defined by the appended claims.
Example 1:
the existing reaction liquid sample of 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt for 4h has the conversion rate of ethyl trifluoroacetoacetate estimated to be 50% according to the synthesis process by a synthesizer, the accurate reaction process is required to be known, and the detection and analysis are carried out by adopting a nuclear magnetic resonance fluorine spectrometry, and the specific steps comprise:
(1) Accurately weighing 35.79mg of internal standard 4-trifluoromethyl nicotinic acid with the content of 98.24 percent and 267.8mg of 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt into a sample bottle, adding 0.4mL of deuterated dimethyl sulfoxide for dissolution, transferring to a nuclear magnetic resonance tube, and detecting nuclear magnetic resonance. 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 sampling point number is 64K.
(2) As shown in fig. 1, in the fluorine spectrum, the chemical shift was a quantitative peak of 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt at δ=64.79 ppm; chemical shifts were quantitative peaks for ethyl trifluoroacetoacetate at δ=81.90 and 84.25 ppm; chemical shift was a quantitative peak of 4-trifluoromethyl nicotinic acid at δ=60.84 ppm; the signal peaks are well separated and are symmetrical and uniform, and the requirement of quantitative nuclear magnetism is met. The content of 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt is 12.72%, the content of ethyl trifluoroacetoacetate is 11.42% and the conversion rate of ethyl trifluoroacetoacetate is 51.94% according to the content calculation formula (a). The samples were repeated 6 times with a standard deviation of 0.29% and a relative standard deviation of 0.21%.
Example 2:
the existing reaction liquid sample of 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt for 16h has the conversion rate of ethyl trifluoroacetoacetate estimated to be about 80 percent according to the synthesis process by a synthesizer, and the accurate reaction process is required to be known, and nuclear magnetic resonance is adopted for detection and analysis, and the specific steps comprise:
(1) Accurately weighing 25.78mg of internal standard N-methyl-N- (trimethylsilyl) trifluoroacetamide with the content of 97.50 percent and 310.2mg of 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt into a sample bottle, adding 0.4mL of deuterated methanol for dissolution, transferring to a nuclear magnetic resonance tube, and detecting nuclear magnetic resonance. 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 sampling point number is 64K.
(2) As shown in fig. 2, in the fluorine spectrum, the chemical shift was a quantitative peak of 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt at δ=66.83 ppm; chemical shift is a quantitative peak of ethyl trifluoroacetoacetate at δ= 83.73 ppm; chemical shift at δ= 77.32ppm is the quantitative peak of the internal standard N-methyl-N- (trimethylsilyl) trifluoroacetamide; the signal peaks are well separated and are symmetrical and uniform, and the requirement of quantitative nuclear magnetism is met. According to the content calculation formula (a), the content of 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt is 27.03%, the content of ethyl trifluoroacetoacetate is 2.62%, and the conversion rate of the ethyl trifluoroacetoacetate is 88.98%. The samples were repeated 6 times with a standard deviation of 0.16% and a relative standard deviation of 0.19%.
Example 3:
the existing reaction liquid sample of 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt for 24h needs to know the accurate reaction process by a synthesizer, and the detection and analysis are carried out by nuclear magnetic resonance, and the specific steps comprise:
(1) Accurately weighing 315.20mg of the reaction solution of the internal standard ciprofloxacin 13.10mg and 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt with the content of 98.10 percent into a sample bottle, adding 0.4mL of deuterated dimethyl sulfoxide, dissolving, transferring to a nuclear magnetic resonance 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 sampling point number is 64K.
(2) As shown in fig. 3, in the fluorine spectrum, the chemical shift was a quantitative peak of 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt at δ= 64.59 ppm; chemical shift is a quantitative peak of ethyl trifluoroacetoacetate at δ=84.01 ppm; chemical shift is a quantitative peak of the internal standard ciprofloxacin at δ= 121.90 ppm; the signal peaks are well separated and are symmetrical and uniform, and the requirement of quantitative nuclear magnetism is met. According to the content calculation formula (a), the content of the 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt is 34.59 percent, the content of the ethyl trifluoroacetoacetate is 1.04 percent, and the conversion rate of the ethyl trifluoroacetoacetate is as follows: 95.62%. Repeated 6 times with a standard deviation of 0.25% and a relative standard deviation of 0.23%.
Comparative example 1:
preparing a reaction liquid sample of 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt with known content, and adopting nuclear magnetic resonance for detection and analysis, wherein the specific steps comprise:
(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 total sample mass is 78.27mg, the proportion of 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt is 50.40%, the proportion of ethyl trifluoroacetoacetate is 47.43%, and 0.4mL of deuterated dimethyl sulfoxide is added for dissolution and then transferred to a 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 sampling point number is 32K.
(2) As shown in fig. 4, in the fluorine spectrum, the chemical shift was a quantitative peak of 3-cyano-2, 6-dihydroxy-4-trifluoromethylpyridine triethylamine salt at δ=64.79 ppm; chemical shifts were quantitative peaks for ethyl trifluoroacetoacetate at δ=81.90 and 84.25 ppm; chemical shift was a quantitative peak of 4-trifluoromethyl nicotinic acid at δ=60.84 ppm; the signal peaks are well separated and are symmetrical and uniform, and the requirement of quantitative nuclear magnetism is met. The actual measurement content of 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt is 39.29 percent and the actual measurement content of ethyl trifluoroacetoacetate is 38.64 percent according to the content calculation formula (a). Repeated for 6 times, the recovery rate of the 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt is 77.97 percent, and the recovery rate of the ethyl trifluoroacetoacetate is 81.45 percent, so that the accuracy is poor.
Comparative example 2:
experiments prove that besides the deuterated dimethyl sulfoxide and the deuterated methanol, the deuterated ethanol is also a good solvent, but the deuterated ethanol is not selected from the cost consideration due to the high price. The other deuterated reagents, namely deuterated acetonitrile, deuterated acetone, deuterated pyridine, deuterated benzene, deuterated toluene or deuterated methylene dichloride, have different degrees of cracking, do not meet the quantitative requirement, and as shown in fig. 5, 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt and ethyl trifluoroacetoacetate have different degrees of cracking under the deuterated acetonitrile solvent, and accurate quantitative results are difficult to obtain through integration.
Table 1 parameters of deuterated reagents and internal standard substances used in examples and comparative examples
The foregoing is merely a preferred embodiment of the present invention, and it should be noted that modifications and improvements could be made by those skilled in the art without departing from the inventive concept, which falls within the scope of the present invention.
Claims (3)
1. A process control method for synthesizing 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt is characterized in that quantitative nuclear magnetic resonance fluorine spectrometry is adopted to simultaneously determine the conversion rate of raw materials, the raw materials and the product content; wherein the raw material is ethyl trifluoroacetoacetate; the quantitative nuclear magnetic resonance fluorine spectrometry comprises the following steps:
(1) Preparing a solution: dissolving 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt reaction liquid and an internal standard substance in a deuteration reagent, transferring to a nuclear magnetic tube, and measuring by nuclear magnetic fluorine spectrum;
(2) Setting nuclear magnetic resonance 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 (3) result processing: after the measurement is finished, determining characteristic peaks of the raw materials, the products and the internal standard substances, calculating peak areas, and calculating to obtain the conversion rate of the raw materials, the contents of the raw materials and the products;
the internal standard is one or more of 2-chloro-4-trifluoromethyl benzonitrile, N-methyl-N- (trimethylsilyl) trifluoroacetamide, benzotrifluoride, ciprofloxacin, 4-trifluoromethyl nicotinic acid or 2, 6-dichloro-3-cyano-4-trifluoromethyl pyridine; the dosage of the 3-cyano-2, 6-dihydroxy-4-trifluoromethyl pyridine triethylamine salt reaction solution is 100-500 mg; the dosage of the internal standard substance is 10-40 mg; the dosage of the deuteration reagent is 0.3-0.8 mL; 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; the sampling spectrum width is 237.16ppm, the sampling center frequency is-100.00 ppm, and the sampling point number is 64K; 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.
2. The method of claim 1, wherein the internal standard is 4-trifluoromethyl nicotinic acid, N-methyl-N- (trimethylsilyl) trifluoroacetamide, or ciprofloxacin.
3. The method of claim 1, wherein the deuterating agent is deuterated methanol or deuterated dimethyl sulfoxide.
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