CN113461615A - Preparation method of 4-fluoro-1H-pyrazole - Google Patents
Preparation method of 4-fluoro-1H-pyrazole Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- RYXJXPHWRBWEEB-UHFFFAOYSA-N 4-fluoro-1h-pyrazole Chemical compound FC=1C=NNC=1 RYXJXPHWRBWEEB-UHFFFAOYSA-N 0.000 title abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 20
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 13
- 239000002253 acid Substances 0.000 claims abstract description 9
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000005580 one pot reaction Methods 0.000 claims abstract description 5
- 239000012363 selectfluor Substances 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 25
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 20
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 claims description 14
- LIAWOTKNAVAKCX-UHFFFAOYSA-N hydrazine;dihydrochloride Chemical compound Cl.Cl.NN LIAWOTKNAVAKCX-UHFFFAOYSA-N 0.000 claims description 13
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 8
- 239000006227 byproduct Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- WVGCPEDBFHEHEZ-UHFFFAOYSA-N 4-bromo-1h-pyrazole Chemical compound BrC=1C=NNC=1 WVGCPEDBFHEHEZ-UHFFFAOYSA-N 0.000 claims description 6
- LLNQWPTUJJYTTE-UHFFFAOYSA-N 4-iodopyrazole Chemical compound IC=1C=NNC=1 LLNQWPTUJJYTTE-UHFFFAOYSA-N 0.000 claims description 6
- 238000004821 distillation Methods 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 239000012025 fluorinating agent Substances 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 abstract description 5
- 239000011737 fluorine Substances 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 4
- XHTYQFMRBQUCPX-UHFFFAOYSA-N 1,1,3,3-tetramethoxypropane Chemical compound COC(OC)CC(OC)OC XHTYQFMRBQUCPX-UHFFFAOYSA-N 0.000 abstract description 3
- 125000003226 pyrazolyl group Chemical group 0.000 abstract description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 abstract 1
- 230000007062 hydrolysis Effects 0.000 abstract 1
- 238000006460 hydrolysis reaction Methods 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 5
- 238000009835 boiling Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- VCYZVXRKYPKDQB-UHFFFAOYSA-N ethyl 2-fluoroacetate Chemical compound CCOC(=O)CF VCYZVXRKYPKDQB-UHFFFAOYSA-N 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- JGFYQVQAXANWJU-UHFFFAOYSA-M sodium fluoroacetate Chemical compound [Na+].[O-]C(=O)CF JGFYQVQAXANWJU-UHFFFAOYSA-M 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- CSUFEOXMCRPQBB-UHFFFAOYSA-N 1,1,2,2-tetrafluoropropan-1-ol Chemical compound CC(F)(F)C(O)(F)F CSUFEOXMCRPQBB-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- QMQZXWWFXNWPMP-UHFFFAOYSA-N 3-(dimethylamino)-2-fluoroprop-2-enal Chemical compound CN(C)C=C(F)C=O QMQZXWWFXNWPMP-UHFFFAOYSA-N 0.000 description 1
- WNDHCIJGEKNYNF-UHFFFAOYSA-N 5-fluoro-1h-pyrazole Chemical class FC=1C=CNN=1 WNDHCIJGEKNYNF-UHFFFAOYSA-N 0.000 description 1
- 108050006749 Alpha 1A adrenoceptor Proteins 0.000 description 1
- 102100024349 Alpha-1A adrenergic receptor Human genes 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000037196 Medullary thyroid carcinoma Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- -1 fluorinated pyrazole ring compound Chemical class 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- GBLBJPZSROAGMF-BATDWUPUSA-N pralsetinib Chemical compound CO[C@]1(CC[C@@H](CC1)C1=NC(NC2=NNC(C)=C2)=CC(C)=N1)C(=O)N[C@@H](C)C1=CC=C(N=C1)N1C=C(F)C=N1 GBLBJPZSROAGMF-BATDWUPUSA-N 0.000 description 1
- 229940121597 pralsetinib Drugs 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 208000013818 thyroid gland medullary carcinoma Diseases 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D231/16—Halogen atoms or nitro radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a preparation method of 4-fluoro-1H-pyrazole, and particularly relates to an effective method for preparing 4-fluoro-1H-pyrazole (compound I) by using a one-pot method, which comprises the following steps: concentrated hydrochloric acid is selected as acid, Selectfluor is selected as a fluorinating reagent, and the 4-fluoro-1H-pyrazole (compound I) is prepared from 1,1,3, 3-tetramethoxy propane (compound II) through hydrolysis and a one-pot method for closing pyrazole ring by fluorine. The method has the advantages of convenient operation and stable yield, and is suitable for industrial production.
Description
Technical Field
The invention relates to the field of synthesis of drug intermediates, in particular to a preparation method of 4-fluoro-1H-pyrazole.
Background
In recent years, researches and experiments find that compounds with a pyrazole ring as a key segment of a molecule have wide application in various stages of drug development, the compounds have wide biological activity, and the diversity change of substitution sites and substituents on the pyrazole ring makes the marketed pyrazole compounds increasingly abundant, so that the compounds have high practical value.
Fluorine atoms are introduced due to strong electronegativity and small atomic radius, and lipophilicity and metabolic stability of the fluorine atoms can be improved by introducing the fluorine atoms or fluorine-containing molecules, so that the fluorine atoms or fluorine-containing molecules are often applied to structure optimization of compounds, and physicochemical properties of the compounds and drug effects, toxicity, metabolic processes and the like of drug molecules are improved. Therefore, the fluorinated pyrazole ring compound has great potential as a medicament development structure optimization intermediate.
4-fluoro-1H-pyrazole is a class of fluoro-pyrazole compounds, is used for research and development of various medicaments in recent years, and has wide market prospect. A representative drug, Pralsetinib (Compound IV), in which 4-fluoro-1H-pyrazole is a key molecular fragment, is an oral RET inhibitor developed by Blueprint medicins; the medicine can be used for treating RET fusion positive non-small cell lung cancer (NSCLC), and is already in phase III clinical trial stage in the United states in 1 month of 2020; meanwhile, the medicine is used for treating medullary thyroid carcinoma and other RET-modified solid tumor patients, and is also under early clinical development. The literature Tetrahedron Letters (2010),51(21),2849-2851 discloses compounds V, which are novel 2-imidazoles and can act as potent, selective and central nervous system permeable partial agonists of the α 1A adrenoceptor.
At present, there are two main methods reported in the literature to be applicable to the large-scale production of 4-fluoro-1H-pyrazole.
Method 1
Patent WO2013043624a1 discloses the following synthesis:
taking ethyl fluoroacetate as a starting material, and hydrolyzing the ethyl fluoroacetate into sodium salt to generate an intermediate sodium fluoroacetate; reacting sodium fluoroacetate with oxalyl chloride and DMF to generate 3- (dimethylamino) -2-fluoroprop-2-enal; finally reacting with hydrazine dihydrochloride to generate a target product. In the route, the ethyl fluoroacetate serving as the starting raw material and the sodium fluoroacetate serving as the product in the first step belong to high-toxicity chemicals, so that the method has great harm to the body and has safety risk in operation. In addition, the total yield of the route is low, only 20 percent, and the route is not suitable for industrial production.
Method two
Using tetrafluoropropanol as an initial raw material, firstly reacting with p-toluenesulfonyl chloride, and generating a compound 2 after hydroxyl protection; under the ultralow temperature condition of minus 85 ℃, the compound 2 reacts with butyl lithium to generate fluorine elimination reaction, and then a compound 3 is generated; reacting the compound 3 with TBFA and diethylamine to generate a compound 4; the compound 4 finally reacts with hydrazine dihydrochloride to generate a target product. The route has 4 steps of reaction, and the total yield is 23.7%; wherein the second step of the reaction with butyl lithium needs to be strictly controlled at ultralow temperature (lower than-80 ℃), otherwise a large amount of byproducts are generated, and the process has high requirements on equipment, so that the process is not suitable for industrial production.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to overcome the defects in the prior art and provide an improved method for preparing 4-fluoro-1H-pyrazole (compound I), which has the advantages of easily available raw materials, simple and convenient operation, high product purity (up to 99 percent) and high total yield (up to 45 percent) and is suitable for large-scale preparation.
The invention provides a preparation method of a compound I, which comprises the following steps:
wherein the acid is selected from concentrated hydrochloric acid; the fluorinating reagent is selected from Selectfluor reagent;
after the compound II reacts with a fluorinating reagent under the action of acid, hydrazine dihydrochloride is added.
Preferably, water is used as the solvent.
Preferably, the reaction is carried out using a one-pot process.
Preferably, the molar ratio of the compound II, the acid, the fluorinating reagent and the hydrazine dihydrochloride is 1: 1-1.2: 1.0-1.5: 1.0-1.2.
Preferably, the compound II reacts with a fluorinating reagent under the action of acid, and the reaction temperature ranges from 20 ℃ to 50 ℃; the reaction time is 1-3 h.
Preferably, the hydrazine dihydrochloride is added, and the hydrazine dihydrochloride is added at one time;
preferably, after hydrazine dihydrochloride is added, the reaction temperature ranges from 10 ℃ to 30 ℃; the reaction time is 1-2 h;
preferably, after the reaction is finished, adding N-bromosuccinimide or N-iodosuccinimide to react with the byproduct pyrazole generated by the reaction to generate 4-bromopyrazole or 4-iodopyrazole;
preferably, after the byproduct pyrazole and N-bromosuccinimide or N-iodosuccinimide react to generate 4-bromopyrazole or 4-iodopyrazole, reduced pressure distillation is adopted for purification, and the pressure range is 50-400 Pa.
The inventor analyzes the reaction impurities and finds that after the reaction is finished, pyrazole is the only by-product difficult to remove in the route, and because the difference between hydrogen and fluorine is small, impurities are difficult to effectively remove through recrystallization, pH adjustment and distillation; after the reaction is finished and is pretreated, NBS or NIS is added into the system, and pyrazole and the NBS or NIS react to generate 4-bromopyrazole or 4-iodopyrazole; due to the fact that pyrazole (with a boiling point of 186-188 ℃), 4-fluoropyrazole (with a boiling point of 193 ℃), 4-bromopyrazole (with a boiling point of 250-260 ℃) and 4-iodopyrazole (with a boiling point of 290-300 ℃) are adopted, a high-purity target compound can be obtained smoothly through a reduced pressure distillation method by utilizing the difference of the boiling points of the compounds, the purification difficulty is greatly reduced, and the purity of a final product can reach 99%.
Advantageous effects
According to the preparation method of the 4-fluoro-1H-pyrazole (compound I), 1,3, 3-tetramethoxypropane (compound II) is selected as an initial raw material, so that the raw material is simple and easy to obtain and is low in price; compared with the existing process for synthesizing 4-fluoro-1H-pyrazole, the one-pot reaction for preparing the 4-fluoro-1H-pyrazole has obvious advantages. In the prior art, raw materials which are harmful to human bodies are used, the target product can be obtained only through 3-5 steps of synthesis, the production period is long, only 3 days are needed for 10 kg production, and the purification is performed for 3 days (the same amount of the prior art needs at least 5 weeks); in addition, reagents such as butyl lithium and the like are not needed, harsh reaction conditions are avoided, production can be carried out only by using a common reaction kettle, and cost is reduced. The amount of three wastes is greatly reduced, and the PMI is reduced to 80 from 384 in the prior art; the method has high yield which can reach more than 45 percent and is suitable for industrial production.
Abbreviations for the reagents referred to in the specification are as follows:
NBS: n-bromosuccinimide;
NIS: n-iodosuccinimide;
selectfluor: 1-chloromethyl-4-fluoro-1, 4-diazobicyclo [2.2.2] octane ditetrafluoroborate;
MTBE: methyl tert-butyl ether.
Detailed Description
The present invention will be further illustrated by the following specific examples, which are carried out on the premise of the technical scheme of the present invention, and it should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.
Example 1
Preparation of compound I:
1,1,3, 3-tetramethoxypropane (1.8kg, 10.96mol, 1.0eq.) 139mL of concentrated hydrochloric acid and 2.75L of water were added to a 5L reaction flask at 28 ℃ under nitrogen. Stirring and reacting for 2 hours at the temperature of 20-30 ℃. Adding a Selectfluor reagent (4.66kg, 13.15mol, 1.2eq.) into the reaction system at 20-30 ℃, and continuing the reaction for 2h at 20-30 ℃. Hydrazine dihydrochloride (1.27kg, 12.06mol, 1.1eq.) is quickly added into a reaction bottle, and after the addition is finished, colorless liquid of reaction liquid is changed into wine red liquid and viscous bubbles are generated, and the reaction is stirred for 1 hour at the temperature of 20-30 ℃. And cooling the reaction system to 10-20 ℃, dropwise adding 50% NaOH aqueous solution (380mL), adding 3L of MTBE into the system after dropwise adding, stirring for 1h at 10-20 ℃, filtering with diatomite, separating the filtrate, extracting the aqueous phase with MTBE, combining the organic phases, drying, concentrating and removing the solvent to obtain 945g of crude product. Dissolving the crude product in 2.6L DCM, cooling to 0-10 ℃ in an ice-water bath under the nitrogen atmosphere, adding NBS (156.3g, 0.878mol) into the system, and stirring and reacting for 2-3 h at 0-10 ℃. LC-MS showed the reaction was complete. Concentrating under reduced pressure to remove solvent, distilling under reduced pressure (100-200 Pa) with oil pump, heating at 40-50 deg.C, collecting 38-40 deg.C fraction to obtain compound I as colorless liquid 380.1g, and collectingThe ratio was 40.28%. The purity is 99%.1HNMR(400MHz，DMSO，d6)(ppm)：7.41～7.39(m，2H)。(ESI-TOF)m/z：[M+H]+calcd for C3H3N2F：86；found：87。
Example 2
Preparation of compound I:
in this example, the procedure of the compound I of example 1 was followed, using different amounts of starting materials, adding NBS or NIS after the reaction, reacting with pyrazole produced as a by-product, and purifying to obtain the following results in Table 1.
TABLE 1
Claims (9)
1. A process for the preparation of compound I, comprising:
wherein the acid is selected from concentrated hydrochloric acid; the fluorinating reagent is selected from Selectfluor reagent;
after the compound II reacts with a fluorinating reagent under the action of acid, hydrazine dihydrochloride is added.
2. The production method according to claim 1, characterized in that: water is selected as the solvent.
3. The production method according to claim 1 or claim 2, characterized in that: the reaction was carried out using a one-pot method.
4. The production method according to claim 3, characterized in that: the molar ratio of the compound II, the acid, the fluorinating agent and the hydrazine dihydrochloride is 1: 1-1.2: 1.0-1.5: 1.0-1.2.
5. The method of claim 1, wherein: reacting the compound II with a fluorinating reagent under the action of acid, wherein the reaction temperature is 20-50 ℃; the reaction time is 1-3 h.
6. The production method according to claim 1 or claim 5, characterized in that: and (3) adding hydrazine dihydrochloride, namely adding hydrazine dihydrochloride at one time.
7. The preparation method according to claim 6, wherein the reaction temperature is 10-30 ℃ after the hydrazine dihydrochloride is added; the reaction time is 1-2 h.
8. The method according to claim 1, wherein after completion of the reaction, N-bromosuccinimide or N-iodosuccinimide is added to react with pyrazole produced as a by-product of the reaction to produce 4-bromopyrazole or 4-iodopyrazole.
9. The process according to claim 8, wherein the pyrazole produced as a by-product is reacted with N-bromosuccinimide or N-iodosuccinimide to produce 4-bromopyrazole or 4-iodopyrazole, which is then purified by distillation under reduced pressure.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115974784A (en) * | 2022-12-02 | 2023-04-18 | 苏利制药科技江阴有限公司 | A kind of synthetic method of 4-fluoro-1H-pyrazole |
| CN116514717A (en) * | 2022-01-28 | 2023-08-01 | F.I.S.-菲博利佳意大利合成面料股份公司 | Efficient process for preparing 4-fluoro-1H-pyrazoles or salts thereof |
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2020
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116514717A (en) * | 2022-01-28 | 2023-08-01 | F.I.S.-菲博利佳意大利合成面料股份公司 | Efficient process for preparing 4-fluoro-1H-pyrazoles or salts thereof |
| CN115974784A (en) * | 2022-12-02 | 2023-04-18 | 苏利制药科技江阴有限公司 | A kind of synthetic method of 4-fluoro-1H-pyrazole |
| CN115974784B (en) * | 2022-12-02 | 2025-04-11 | 苏利制药科技江阴有限公司 | A kind of synthetic method of 4-fluoro-1H-pyrazole |
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