CN117946070A - Preparation method of 1- (3-chloropyridine-2-yl) -3-pyrazolone-5-carboxylic acid ethyl ester - Google Patents
Preparation method of 1- (3-chloropyridine-2-yl) -3-pyrazolone-5-carboxylic acid ethyl ester Download PDFInfo
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- -1 3-chloropyridine-2-yl Chemical group 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 107
- XAYCTBDPZIKHCW-UHFFFAOYSA-N (3-chloropyridin-2-yl)hydrazine Chemical compound NNC1=NC=CC=C1Cl XAYCTBDPZIKHCW-UHFFFAOYSA-N 0.000 claims abstract description 54
- 238000000034 method Methods 0.000 claims abstract description 43
- 239000002904 solvent Substances 0.000 claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 claims abstract description 9
- 150000005690 diesters Chemical class 0.000 claims abstract description 8
- 239000000376 reactant Substances 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 117
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 42
- 239000012043 crude product Substances 0.000 claims description 42
- 239000007795 chemical reaction product Substances 0.000 claims description 41
- 239000007787 solid Substances 0.000 claims description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 39
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 32
- 230000008569 process Effects 0.000 claims description 29
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 27
- 229960000583 acetic acid Drugs 0.000 claims description 21
- 238000001914 filtration Methods 0.000 claims description 21
- 239000012362 glacial acetic acid Substances 0.000 claims description 21
- 239000010410 layer Substances 0.000 claims description 21
- 239000012044 organic layer Substances 0.000 claims description 21
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 21
- 239000012141 concentrate Substances 0.000 claims description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 4
- 239000011976 maleic acid Substances 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 230000008901 benefit Effects 0.000 abstract description 5
- 238000007867 post-reaction treatment Methods 0.000 abstract description 4
- 238000010438 heat treatment Methods 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 description 118
- 239000011541 reaction mixture Substances 0.000 description 54
- 239000000047 product Substances 0.000 description 27
- IEPRKVQEAMIZSS-UHFFFAOYSA-N Di-Et ester-Fumaric acid Natural products CCOC(=O)C=CC(=O)OCC IEPRKVQEAMIZSS-UHFFFAOYSA-N 0.000 description 22
- IEPRKVQEAMIZSS-WAYWQWQTSA-N Diethyl maleate Chemical compound CCOC(=O)\C=C/C(=O)OCC IEPRKVQEAMIZSS-WAYWQWQTSA-N 0.000 description 22
- 238000010907 mechanical stirring Methods 0.000 description 18
- 230000001376 precipitating effect Effects 0.000 description 18
- 239000000575 pesticide Substances 0.000 description 14
- 239000007858 starting material Substances 0.000 description 6
- 241000607479 Yersinia pestis Species 0.000 description 5
- 230000002194 synthesizing effect Effects 0.000 description 5
- XXTPHXNBKRVYJI-UHFFFAOYSA-N 2-pyrazol-1-ylpyridine Chemical compound C1=CC=NN1C1=CC=CC=N1 XXTPHXNBKRVYJI-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000007791 liquid phase Substances 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 238000010587 phase diagram Methods 0.000 description 4
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- 239000003054 catalyst Substances 0.000 description 3
- 238000011161 development Methods 0.000 description 3
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- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- BKWTUCBUSLAMGU-UHFFFAOYSA-N 1-pyridin-2-ylpyrazole-3-carboxylic acid Chemical class N1=C(C(=O)O)C=CN1C1=CC=CC=N1 BKWTUCBUSLAMGU-UHFFFAOYSA-N 0.000 description 2
- 239000005886 Chlorantraniliprole Substances 0.000 description 2
- 239000005889 Cyantraniliprole Substances 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 238000012271 agricultural production Methods 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- PSOVNZZNOMJUBI-UHFFFAOYSA-N chlorantraniliprole Chemical compound CNC(=O)C1=CC(Cl)=CC(C)=C1NC(=O)C1=CC(Br)=NN1C1=NC=CC=C1Cl PSOVNZZNOMJUBI-UHFFFAOYSA-N 0.000 description 2
- DVBUIBGJRQBEDP-UHFFFAOYSA-N cyantraniliprole Chemical compound CNC(=O)C1=CC(C#N)=CC(C)=C1NC(=O)C1=CC(Br)=NN1C1=NC=CC=C1Cl DVBUIBGJRQBEDP-UHFFFAOYSA-N 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 230000002147 killing effect Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
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- 238000006798 ring closing metathesis reaction Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- MAKFMOSBBNKPMS-UHFFFAOYSA-N 2,3-dichloropyridine Chemical compound ClC1=CC=CN=C1Cl MAKFMOSBBNKPMS-UHFFFAOYSA-N 0.000 description 1
- 241001124076 Aphididae Species 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 241001477931 Mythimna unipuncta Species 0.000 description 1
- 241000500437 Plutella xylostella Species 0.000 description 1
- 241000985245 Spodoptera litura Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- GSEPHVGFSQHACX-UHFFFAOYSA-N hydrazine;pyridine Chemical compound NN.C1=CC=NC=C1 GSEPHVGFSQHACX-UHFFFAOYSA-N 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 230000000749 insecticidal effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
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- 239000000126 substance Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
Abstract
The invention relates to the technical field of organic synthesis, in particular to a preparation method of 1- (3-chloropyridine-2-yl) -3-pyrazolone-5-carboxylic acid ethyl ester. The invention dissolves 3-chloro-2-hydrazinopyridine in a solvent under alkaline condition, then evenly mixes with maleic diester to obtain a reactant, and obtains 1- (3-chloropyridine-2-yl) -3-pyrazolone-5-carboxylic acid ethyl ester after post-reaction treatment. Compared with the prior art, the preparation method of the 1- (3-chloropyridine-2-yl) -3-pyrazolone-5-carboxylic acid ethyl ester adopts a stage heating method and a unique post-reaction treatment mode, so that the yield of a target product is improved. In general, the method has the advantages of simple operation, mild reaction conditions, high yield, little pollution and easy industrialized production.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of 1- (3-chloropyridine-2-yl) -3-pyrazolone-5-carboxylic acid ethyl ester.
Background
Chemical pest control is a widely used pest control mode in modern agricultural production, but with the frequent use of pesticides, pests have developed different degrees of resistance to the pesticide, so there is an urgent need to develop pesticides with new mechanisms of action. At present, nitrogen-containing heterocycles are one of the hot problems in the research of novel pesticide pesticides due to the broad spectrum of biological activity. The N-pyridylpyrazole is used as an important nitrogen-containing heterocyclic unit, has wide application prospect in the fields of agricultural production and the like, and has wide insecticidal effects on insect pests such as armyworm, aphid, prodenia litura and the like by chlorantraniliprole (Chlorantraniliprole) and cyantraniliprole (Cyantraniliprole). Meanwhile, the pesticide of the type has no mutual resistance with other traditional pesticides, and has the advantages of high efficiency, low toxicity and the like, so that the pesticide has also received great attention from scientific researchers. In recent years, many N-pyridylpyrazole derivatives having a wide range of biological activities have been developed, such as compound A reported by the Kang group of topics (Eur J. Med. Chem.2013,67,14-18) having a killing rate of 100% on plutella xylostella at a test concentration of 100. Mu.g/mL; compound B synthesized by Zhang et al (J.Agric.food chem.2012,60, 7565-7572) had 100% killing activity against myxoplasma at a test concentration of 200. Mu.g/mL.
The novel efficient and safe pesticide N-pyridylpyrazole carboxylic acid derivative not only can accurately and even precisely attack and control target pests, but also is very friendly to other organisms and ecological environments, has the characteristic of 'no residual toxicity' and other comprehensive excellent physicochemical properties, so that the compound has the special quality of 'ecological pesticides', and has very broad market prospect. However, from literature studies, it was found that ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate is one of the key intermediates for the synthesis of these numbers, known as "ecological pesticides". Therefore, the development of an excellent and efficient route for synthesizing ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate, and thus obtaining an N-pyridylpyrazolecarboxylic acid derivative with better quality and lower price is an urgent research subject currently by pesticide synthesis specialists. Therefore, there is still a need to find a more advanced and reasonable preparation method of the target compound or to optimize the original reaction route in order to obtain the pesticide service of the N-pyridylpyrazole derivative with better quality and lower production price. Meanwhile, the development of a process route for synthesizing the 1- (3-chloropyridine-2-yl) -3-pyrazolone-5-carboxylic acid ethyl ester can also show the characteristics of simple operation, improvement of product yield, low cost, suitability for industrial production and the like.
In the past, the process routes for synthesizing the 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylic acid ethyl ester are more, but the process routes also have the characteristics, advantages and disadvantages:
(1) Patent CN110615780 discloses that the target product is obtained by using maleic anhydride as a starting material and through a series of processes of esterification, bromination, acyl chlorination and the like, the synthetic route has a plurality of steps, the reaction conditions are harsh, and the reaction time is long.
(2) In CN106831705, a method using maleic anhydride as a starting material is disclosed, and the synthesis route is different although the same maleic anhydride is used as the starting material, and the target product is finally obtained, compared with the first method.
(3) Patent CN110396079 discloses a process using diethyl maleate and hydrazine hydrate as starting materials, which has the main disadvantage of low cyclization yield despite the readily available sources of the starting materials and short steps.
(4) Indian patent IN201821028730 discloses that target products are obtained by taking monopyridine ethylhydrazide of maleic acid as a raw material, but the method adds one step of hydrogen bromide addition, so that the cost for producing the target products is increased.
(5) Patent CN1023114 discloses a method using diethyl maleate and 3-chloro-2-hydrazinopyridine as starting materials, which is the most commonly used method at present, and pyridine hydrazine and diethyl maleate which are easily obtained from raw materials or dichloropyridine react with hydrazine hydrate first and then react with diethyl maleate under alkaline condition to obtain the target product.
It has been found that although there are many routes for synthesizing ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate, some of these routes have disadvantages such as longer routes, lower yields, excessive costs of raw materials and routes, difficult sources, complicated production processes, severe conditions, difficult process amplification, etc., but there are still attractive routes for the synthesis, such as fifth. However, it has been found that, although the fifth synthetic route has a great advantage, it also has a problem that the ring closure of the reaction intermediate is difficult, resulting in a low yield of the objective product. Although some documents report the addition of a catalyst (patent CN 106928183) at the time of the reaction to solve the problem of difficult ring closure, it has also been found that the catalyst must be prepared, which in turn adds to the cost of the reaction, and finally does not practically increase the yield of the reaction. Therefore, there is still a need to find a more advanced and reasonable preparation method of the target compound or to optimize the original reaction route in order to obtain the N-pyridylpyrazole derivative pesticide with better quality and lower production price. Meanwhile, the development of a process route for synthesizing the 1- (3-chloropyridine-2-yl) -3-pyrazolone-5-carboxylic acid ethyl ester can also show the characteristics of simple operation, improvement of product yield, low cost, suitability for industrial production and the like.
Disclosure of Invention
In order to solve the above problems, an object of the present invention is to provide a process for preparing ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate. The invention dissolves 3-chloro-2-hydrazinopyridine in a solvent under alkaline condition, then evenly mixes with maleic diester to obtain a reactant, and obtains 1- (3-chloropyridine-2-yl) -3-pyrazolone-5-carboxylic acid ethyl ester after post-reaction treatment. Compared with the prior art, the preparation method of the 1- (3-chloropyridine-2-yl) -3-pyrazolone-5-carboxylic acid ethyl ester adopts a stage heating method and a unique post-reaction treatment mode, so that the yield of a target product is improved. In general, the method has the advantages of simple operation, mild reaction conditions, high yield, little pollution and easy industrialized production.
The aim of the invention can be achieved by the following technical scheme:
The invention provides a preparation method of 1- (3-chloropyridine-2-yl) -3-pyrazolidinone-5-carboxylic acid ethyl ester, which comprises the following steps:
Dissolving 3-chloro-2-hydrazinopyridine in a solvent under an alkaline condition, uniformly mixing with maleic diester to obtain a reactant, and performing post-treatment after the reaction to obtain 1- (3-chloropyridine-2-yl) -3-pyrazolidinone-5-carboxylic acid ethyl ester;
In one embodiment of the invention, sodium ethoxide is added to the solvent.
In one embodiment of the invention, the solvent is ethanol.
In one embodiment of the invention, the molar ratio of 3-chloro-2-hydrazinopyridine to sodium ethoxide is 1:1 to 1.3;
preferably, the molar ratio of 3-chloro-2-hydrazinopyridine to sodium ethoxide is 1:1.2.
In one embodiment of the invention, the molar ratio of 3-chloro-2-hydrazinopyridine to maleic acid diester is 1:1.4 to 1.5;
preferably, the molar ratio of 3-chloro-2-hydrazinopyridine to maleic diester is 1:1.45.
In one embodiment of the invention, the reaction is carried out at a temperature of 20 to 70 ℃ for a time of 6 to 8 hours.
In one embodiment of the invention, the reaction process is a stepwise elevated temperature reaction process, including a first reaction process, a second reaction process, and a third reaction process.
In one embodiment of the invention, the temperature is 25 ℃ and the time is 1h during the first reaction;
In the second reaction process, the temperature is 40 ℃ and the time is 2 hours;
in the third reaction process, the temperature is 70 ℃ and the time is 3 hours.
In one embodiment of the invention, after the post-treatment is finished, the reaction product is dropwise added with glacial acetic acid under ice bath to precipitate solid, and the solid is continuously concentrated under the water bath condition to obtain concentrate; then dissolving the concentrate, and filtering to obtain a crude product; the crude product was redissolved, washed with saturated brine, the aqueous layer extracted with dichloromethane, the organic layers combined and concentrated to give ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate.
Compared with the prior art, the invention has the following beneficial effects:
The preparation method of the 1- (3-chloropyridine-2-yl) -3-pyrazolone-5-carboxylic acid ethyl ester does not need a catalyst or an additive in the reaction, has mild reaction conditions, and has the characteristics of higher yield and the like compared with the traditional method using the same raw material. In addition, the reaction operation is convenient, the post-treatment is more convenient, and the large-scale production can be realized.
Drawings
FIG. 1 is a liquid phase diagram of a 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylic acid ethyl ester standard;
FIG. 2 is a liquid phase diagram of the reaction product prepared in example 1;
FIG. 3 is a nuclear magnetic resonance spectrum (1 HNMR) of ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate prepared in example 1;
FIG. 4 is a nuclear magnetic resonance spectrum (1 CNMR) of ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate prepared in example 1.
Detailed Description
The invention provides a preparation method of 1- (3-chloropyridine-2-yl) -3-pyrazolidinone-5-carboxylic acid ethyl ester, which comprises the following steps:
Dissolving 3-chloro-2-hydrazinopyridine in a solvent under an alkaline condition, uniformly mixing with maleic diester to obtain a reactant, and performing post-treatment after the reaction to obtain 1- (3-chloropyridine-2-yl) -3-pyrazolidinone-5-carboxylic acid ethyl ester;
further, sodium ethoxide is added to the solvent.
Further, the solvent is ethanol.
Further, the molar ratio of 3-chloro-2-hydrazinopyridine to sodium ethoxide is 1:1 to 1.3;
preferably, the molar ratio of 3-chloro-2-hydrazinopyridine to sodium ethoxide is 1:1.2.
Further, the molar ratio of 3-chloro-2-hydrazinopyridine to maleic diester is 1:1.4 to 1.5;
preferably, the molar ratio of 3-chloro-2-hydrazinopyridine to maleic diester is 1:1.45.
Further, the reaction process is carried out at the temperature of 20-70 ℃ for 6-8 hours.
Further, the reaction process is a stepwise temperature-rising reaction process, and comprises a first reaction process, a second reaction process and a third reaction process.
Further, in the first reaction process, the temperature is 25 ℃ and the time is 1h;
In the second reaction process, the temperature is 40 ℃ and the time is 2 hours;
in the third reaction process, the temperature is 70 ℃ and the time is 3 hours.
Further, after the post-treatment is finished, dropwise adding glacial acetic acid into a reaction product under an ice bath to precipitate solid, and continuously concentrating under the water bath condition to obtain a concentrate; then dissolving the concentrate, and filtering to obtain a crude product; the crude product was redissolved, washed with saturated brine, the aqueous layer extracted with dichloromethane, the organic layers combined and concentrated to give ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate.
The present invention will be described in detail with reference to specific examples.
In the examples below, unless otherwise specified, all reagents used were commercially available, and all detection means and methods used were conventional in the art.
The reaction equations involved in the examples below are as follows:
Example 1
This example provides a process for the preparation of ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate comprising the steps of:
(S1) adding 7g of sodium ethoxide (0.102 mol) and 100mL of ethanol to a reaction flask placed with mechanical stirring at 25 ℃ to obtain a reaction mixture;
(S2) after stirring and dissolving the reaction mixture obtained in the step (S1), 10g (0.070 mol) of 3-chloro-2-hydrazinopyridine is added into a reaction bottle in batches, after stirring for 25 minutes, 14.4g (0.084 mol) of diethyl maleate is added into the reaction mixture dropwise, stirring is continued for 1 hour at 25 ℃, then the reaction temperature is increased to 40 ℃ and stirring is continued for 2 hours, and then the reaction temperature is increased to 70 ℃ and stirring is continued for 3 hours, so that a reaction product is obtained;
(S3) placing the reaction product prepared in the step (S2) under ice bath, stirring for 20 minutes, then dropwise adding 7mL of glacial acetic acid, precipitating solid, concentrating the solid to dryness under the condition that the water bath is lower than 50 ℃, adding 10mL of water into the residue, fully stirring, and filtering to obtain a crude product;
(S4) the crude product obtained in the step (S3) was then dissolved in 50mL of methylene chloride, washed with 10mL of saturated brine, separated, the aqueous layer was extracted twice with methylene chloride (20 mL,2 times), and the organic layers were combined and concentrated to dryness to give 14.8g (79% as 3-chloro-2-hydrazinopyridine) of the pure target product.
1H NMR(401MHz,CDCl3)δ8.70(s,1H),8.21(d,J＝4.8Hz,1H),7.67(d,J＝7.8Hz,1H),7.02(dd,J＝7.9,4.5Hz,1H),5.24-5.17(m,1H),4.28(q,J＝7.2Hz,2H),3.14-3.04(m,1H),2.73(dd,J＝17.1,3.0Hz,1H),1.29(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ172.03,170.20,155.32,145.56,139.38,120.91,120.51,61.93,33.83,14.15.
FIG. 1 is a liquid phase diagram of a 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylic acid ethyl ester standard; FIG. 2 is a liquid phase diagram of the reaction product prepared in this example; FIG. 3 is a nuclear magnetic resonance spectrum (1 HNMR) of ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate prepared in this example; FIG. 4 is a nuclear magnetic resonance spectrum (1 CNMR) of ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate prepared in this example; the successful preparation of 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylic acid ethyl ester in this example can be demonstrated by FIGS. 1-4.
Example 2
This example provides a process for the preparation of ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate comprising the steps of:
(S1) adding 7g of sodium ethoxide (0.102 mol) and 100mL of ethanol to a reaction flask placed with mechanical stirring at 25 ℃ to obtain a reaction mixture;
(S2) after stirring and dissolving the reaction mixture obtained in the step (S1), 10g (0.070 mol) of 3-chloro-2-hydrazinopyridine is added into a reaction bottle in batches, after stirring for 25 minutes, 14.4g (0.084 mol) of diethyl maleate is added into the reaction mixture dropwise, and stirring is continued for 6 hours at 25 ℃ to obtain a reaction product;
(S3) placing the reaction product prepared in the step (S2) under ice bath, stirring for 20 minutes, then dropwise adding 7mL of glacial acetic acid, precipitating solid, concentrating the solid to dryness under the condition that the water bath is lower than 50 ℃, adding 10mL of water into the residue, fully stirring, and filtering to obtain a crude product;
(S4) the crude product obtained in the step (S3) was then dissolved in 50mL of methylene chloride, washed with 10 mL of saturated brine, separated, the aqueous layer was extracted twice with methylene chloride (20 mL,2 times), and the organic layers were combined and concentrated to dryness to give 2.2g (12% as 3-chloro-2-hydrazinopyridine) of the pure target product.
Example 3
This example provides a process for the preparation of ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate comprising the steps of:
(S1) adding 7g of sodium ethoxide (0.102 mol) and 100mL of ethanol to a reaction flask placed with mechanical stirring at 25 ℃ to obtain a reaction mixture;
(S2) after stirring and dissolving the reaction mixture obtained in the step (S1), 10g (0.070 mol) of 3-chloro-2-hydrazinopyridine is added into a reaction bottle in batches, after stirring for 25 minutes, 14.4g (0.084 mol) of diethyl maleate is added into the reaction mixture dropwise, and stirring is continued for 6 hours at 40 ℃ to obtain a reaction product;
(S3) placing the reaction product prepared in the step (S2) under ice bath, stirring for 20 minutes, then dropwise adding 7mL of glacial acetic acid, precipitating solid, concentrating the solid to dryness under the condition that the water bath is lower than 50 ℃, adding 10mL of water into the residue, fully stirring, and filtering to obtain a crude product;
(S4) the crude product obtained in the step (S3) was then dissolved in 50mL of methylene chloride, washed with 10 mL of saturated brine, separated, the aqueous layer was extracted twice with methylene chloride (20 mL,2 times), and the organic layers were combined and concentrated to dryness to give 11.6g (62% as 3-chloro-2-hydrazinopyridine) of the pure target product.
Example 4
This example provides a process for the preparation of ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate comprising the steps of:
(S1) adding 7g of sodium ethoxide (0.102 mol) and 100mL of ethanol to a reaction flask placed with mechanical stirring at 25 ℃ to obtain a reaction mixture;
(S2) after stirring and dissolving the reaction mixture obtained in the step (S1), 10g (0.070 mol) of 3-chloro-2-hydrazinopyridine is added into a reaction bottle in batches, after stirring for 25 minutes, 14.4g (0.084 mol) of diethyl maleate is added into the reaction mixture dropwise, and stirring is continued for 6 hours at 60 ℃ to obtain a reaction product;
(S3) placing the reaction product prepared in the step (S2) under ice bath, stirring for 20 minutes, then dropwise adding 7mL of glacial acetic acid, precipitating solid, concentrating the solid to dryness under the condition that the water bath is lower than 50 ℃, adding 10mL of water into the residue, fully stirring, and filtering to obtain a crude product;
(S4) the crude product obtained in the step (S3) was then dissolved in 50mL of methylene chloride, washed with 10 mL of saturated brine, separated, the aqueous layer was extracted twice with methylene chloride (20 mL,2 times), and the organic layers were combined and concentrated to dryness to give 13.3g (71% as 3-chloro-2-hydrazinopyridine) of the pure target product.
Example 5
This example provides a process for the preparation of ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate comprising the steps of:
(S1) adding 7g of sodium ethoxide (0.102 mol) and 30mL of ethanol to a reaction flask placed with mechanical stirring at 25 ℃ to obtain a reaction mixture;
(S2) after stirring and dissolving the reaction mixture obtained in the step (S1), 10g (0.070 mol) of 3-chloro-2-hydrazinopyridine is added into a reaction bottle in batches, after stirring for 25 minutes, 14.4g (0.084 mol) of diethyl maleate is added into the reaction mixture dropwise, stirring is continued for 1 hour at 25 ℃, then the reaction temperature is increased to 40 ℃ and stirring is continued for 2 hours, and then the reaction temperature is increased to 70 ℃ and stirring is continued for 3 hours, so that a reaction product is obtained;
(S3) placing the reaction product prepared in the step (S2) under ice bath, stirring for 20 minutes, then dropwise adding 7mL of glacial acetic acid, precipitating solid, concentrating the solid to dryness under the condition that the water bath is lower than 50 ℃, adding 10mL of water into the residue, fully stirring, and filtering to obtain a crude product;
(S4) the crude product obtained in the step (S3) was then dissolved in 50mL of methylene chloride, washed with 10 mL of saturated brine, separated, the aqueous layer was extracted twice with methylene chloride (20 mL,2 times), and the organic layers were combined and concentrated to dryness to give 9.8g (52% as 3-chloro-2-hydrazinopyridine) of the pure target product.
Example 6
This example provides a process for the preparation of ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate comprising the steps of:
(S1) adding 7g of sodium ethoxide (0.102 mol) and 50mL of ethanol to a reaction flask placed with mechanical stirring at 25 ℃ to obtain a reaction mixture;
(S2) after stirring and dissolving the reaction mixture obtained in the step (S1), 10g (0.070 mol) of 3-chloro-2-hydrazinopyridine is added into a reaction bottle in batches, after stirring for 25 minutes, 14.4g (0.084 mol) of diethyl maleate is added into the reaction mixture dropwise, stirring is continued for 1 hour at 25 ℃, then the reaction temperature is increased to 40 ℃ and stirring is continued for 2 hours, and then the reaction temperature is increased to 70 ℃ and stirring is continued for 3 hours, so that a reaction product is obtained;
(S3) placing the reaction product prepared in the step (S2) under ice bath, stirring for 20 minutes, then dropwise adding 7mL of glacial acetic acid, precipitating solid, concentrating the solid to dryness under the condition that the water bath is lower than 50 ℃, adding 10mL of water into the residue, fully stirring, and filtering to obtain a crude product;
(S4) the crude product obtained in the step (S3) was then dissolved in 50mL of methylene chloride, washed with 10mL of saturated brine, separated, the aqueous layer was extracted twice with methylene chloride (20 mL,2 times), and the organic layers were combined and concentrated to dryness to obtain 12.8g (68% as 3-chloro-2-hydrazinopyridine) of the pure target product.
Example 7
This example provides a process for the preparation of ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate comprising the steps of:
(S1) adding 7g of sodium ethoxide (0.102 mol) and 80mL of ethanol to a reaction flask placed with mechanical stirring at 25 ℃ to obtain a reaction mixture;
(S2) after stirring and dissolving the reaction mixture obtained in the step (S1), 10g (0.070 mol) of 3-chloro-2-hydrazinopyridine is added into a reaction bottle in batches, after stirring for 25 minutes, 14.4g (0.084 mol) of diethyl maleate is added into the reaction mixture dropwise, stirring is continued for 1 hour at 25 ℃, then the reaction temperature is increased to 40 ℃ and stirring is continued for 2 hours, and then the reaction temperature is increased to 70 ℃ and stirring is continued for 3 hours, so that a reaction product is obtained;
(S3) placing the reaction product prepared in the step (S2) under ice bath, stirring for 20 minutes, then dropwise adding 7mL of glacial acetic acid, precipitating solid, concentrating the solid to dryness under the condition that the water bath is lower than 50 ℃, adding 10mL of water into the residue, fully stirring, and filtering to obtain a crude product;
(S4) the crude product obtained in the step (S3) was then dissolved in 50mL of methylene chloride, washed with 10mL of saturated brine, separated, the aqueous layer was extracted twice with methylene chloride (20 mL,2 times), and the organic layers were combined and concentrated to dryness to obtain 13.5g (72% as 3-chloro-2-hydrazinopyridine) of the pure target product.
Example 8
This example provides a process for the preparation of ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate comprising the steps of:
(S1) adding 7g of sodium ethoxide (0.102 mol) and 120mL of ethanol to a reaction flask placed with mechanical stirring at 25 ℃ to obtain a reaction mixture;
(S2) after stirring and dissolving the reaction mixture obtained in the step (S1), 10g (0.070 mol) of 3-chloro-2-hydrazinopyridine is added into a reaction bottle in batches, after stirring for 25 minutes, 14.4g (0.084 mol) of diethyl maleate is added into the reaction mixture dropwise, stirring is continued for 1 hour at 25 ℃, then the reaction temperature is increased to 40 ℃ and stirring is continued for 2 hours, and then the reaction temperature is increased to 70 ℃ and stirring is continued for 3 hours, so that a reaction product is obtained;
(S3) placing the reaction product prepared in the step (S2) under ice bath, stirring for 20 minutes, then dropwise adding 7mL of glacial acetic acid, precipitating solid, concentrating the solid to dryness under the condition that the water bath is lower than 50 ℃, adding 10mL of water into the residue, fully stirring, and filtering to obtain a crude product;
(S4) the crude product obtained in the step (S3) was then dissolved in 50mL of methylene chloride, washed with 10mL of saturated brine, separated, the aqueous layer was extracted twice with methylene chloride (20 mL,2 times), and the organic layers were combined and concentrated to dryness to obtain 13.9g (74% as 3-chloro-2-hydrazinopyridine) of the pure target product.
Example 9
This example provides a process for the preparation of ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate comprising the steps of:
(S1) adding 7g of sodium ethoxide (0.102 mol) and 100mL of ethanol to a reaction flask placed with mechanical stirring at 25 ℃ to obtain a reaction mixture;
(S2) after stirring and dissolving the reaction mixture obtained in the step (S1), 10g (0.070 mol) of 3-chloro-2-hydrazinopyridine is added into a reaction bottle in batches, after stirring for 25 minutes, 14.4g (0.084 mol) of diethyl maleate and Cu (PPh 3)2 I (5 mol%) are added into the reaction mixture dropwise, stirring is continued for 1 hour at 25 ℃, then the reaction temperature is increased to 40 ℃ and stirring is continued for 2 hours, and then the reaction temperature is increased to 70 ℃ and stirring is continued for 3 hours, so as to obtain a reaction product;
(S3) placing the reaction product prepared in the step (S2) under ice bath, stirring for 20 minutes, then dropwise adding 7mL of glacial acetic acid, precipitating solid, concentrating the solid to dryness under the condition that the water bath is lower than 50 ℃, adding 10mL of water into the residue, fully stirring, and filtering to obtain a crude product;
(S4) the crude product obtained in the step (S3) was then dissolved in 50mL of methylene chloride, washed with 10 mL of saturated brine, separated, the aqueous layer was extracted twice with methylene chloride (20 mL,2 times), and the organic layers were combined and concentrated to dryness to give 11.6g (62% as 3-chloro-2-hydrazinopyridine) of the pure target product.
Example 10
This example provides a process for the preparation of ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate comprising the steps of:
(S1) adding 7g of sodium ethoxide (0.102 mol) and 100mL of ethanol to a reaction flask placed with mechanical stirring at 25 ℃ to obtain a reaction mixture;
(S2) after stirring and dissolving the reaction mixture obtained in the step (S1), 10g (0.070 mol) of 3-chloro-2-hydrazinopyridine is added into a reaction bottle in batches, after stirring for 25 minutes, 14.4g (0.084 mol) of diethyl maleate and Sc (OTf) 3 (5 mol%) are added into the reaction mixture dropwise, stirring is continued for 1 hour at 25 ℃, then the reaction temperature is increased to 40 ℃ and stirring is continued for 2 hours, and then the reaction temperature is increased to 70 ℃ and stirring is continued for 3 hours, so that a reaction product is obtained;
(S3) placing the reaction product prepared in the step (S2) under ice bath, stirring for 20 minutes, then dropwise adding 7mL of glacial acetic acid, precipitating solid, concentrating the solid to dryness under the condition that the water bath is lower than 50 ℃, adding 10mL of water into the residue, fully stirring, and filtering to obtain a crude product;
(S4) the crude product obtained in the step (S3) was then dissolved in 50mL of methylene chloride, washed with 10mL of saturated brine, separated, the aqueous layer was extracted twice with methylene chloride (20 mL,2 times), and the organic layers were combined and concentrated to dryness to give 11.3g (60% as 3-chloro-2-hydrazinopyridine) of the pure target product.
Example 11
This example provides a process for the preparation of ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate comprising the steps of:
(S1) adding 7g of sodium ethoxide (0.102 mol) and 100mL of ethanol to a reaction flask placed with mechanical stirring at 25 ℃ to obtain a reaction mixture;
(S2) after stirring and dissolving the reaction mixture obtained in the step (S1), 10g (0.070 mol) of 3-chloro-2-hydrazinopyridine is added into a reaction bottle in batches, after stirring for 25 minutes, 12.0g (0.070 mol) of diethyl maleate is added into the reaction mixture dropwise, stirring is continued for 1 hour at 25 ℃, then the reaction temperature is increased to 40 ℃ and stirring is continued for 2 hours, and then the reaction temperature is increased to 70 ℃ and stirring is continued for 3 hours, so that a reaction product is obtained;
(S3) placing the reaction product prepared in the step (S2) under ice bath, stirring for 20 minutes, then dropwise adding 7mL of glacial acetic acid, precipitating solid, concentrating the solid to dryness under the condition that the water bath is lower than 50 ℃, adding 10mL of water into the residue, fully stirring, and filtering to obtain a crude product;
(S4) the crude product obtained in the step (S3) was then dissolved in 50mL of methylene chloride, washed with 10 mL of saturated brine, separated, the aqueous layer was extracted twice with methylene chloride (20 mL,2 times), and the organic layers were combined and concentrated to dryness to give 9.9g (53% as 3-chloro-2-hydrazinopyridine) of the pure target product.
Example 12
This example provides a process for the preparation of ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate comprising the steps of:
(S1) adding 7g of sodium ethoxide (0.102 mol) and 100mL of ethanol to a reaction flask placed with mechanical stirring at 25 ℃ to obtain a reaction mixture;
(S2) after stirring and dissolving the reaction mixture obtained in the step (S1), 10g (0.070 mol) of 3-chloro-2-hydrazinopyridine is added into a reaction bottle in batches, 13.2g (0.077 mol) of diethyl maleate is dropwise added into the reaction mixture after stirring for 25 minutes, stirring is continued for 1 hour at 25 ℃, then the reaction temperature is increased to 40 ℃ and stirring is continued for 2 hours, and then the reaction temperature is increased to 70 ℃ and stirring is continued for 3 hours, so that a reaction product is obtained;
(S3) placing the reaction product prepared in the step (S2) under ice bath, stirring for 20 minutes, then dropwise adding 7mL of glacial acetic acid, precipitating solid, concentrating the solid to dryness under the condition that the water bath is lower than 50 ℃, adding 10mL of water into the residue, fully stirring, and filtering to obtain a crude product;
(S4) the crude product obtained in the step (S3) was then dissolved in 50mL of methylene chloride, washed with 10mL of saturated brine, separated, the aqueous layer was extracted twice with methylene chloride (20 mL,2 times), and the organic layers were combined and concentrated to dryness to obtain 12.5g (67% as 3-chloro-2-hydrazinopyridine) of the pure target product.
Example 13
This example provides a process for the preparation of ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate comprising the steps of:
(S1) adding 7g of sodium ethoxide (0.102 mol) and 100mL of ethanol to a reaction flask placed with mechanical stirring at 25 ℃ to obtain a reaction mixture;
(S2) after stirring and dissolving the reaction mixture obtained in the step (S1), 10g (0.070 mol) of 3-chloro-2-hydrazinopyridine is added into a reaction bottle in batches, after stirring for 25 minutes, 15.7g (0.091 mol) of diethyl maleate is added into the reaction mixture dropwise, stirring is continued for 1 hour at 25 ℃, then the reaction temperature is increased to 40 ℃ and stirring is continued for 2 hours, and then the reaction temperature is increased to 70 ℃ and stirring is continued for 3 hours, so that a reaction product is obtained;
(S3) placing the reaction product prepared in the step (S2) under ice bath, stirring for 20 minutes, then dropwise adding 7mL of glacial acetic acid, precipitating solid, concentrating the solid to dryness under the condition that the water bath is lower than 50 ℃, adding 10mL of water into the residue, fully stirring, and filtering to obtain a crude product;
(S4) the crude product obtained in the step (S3) was then dissolved in 50mL of methylene chloride, washed with 10mL of saturated brine, separated, the aqueous layer was extracted twice with methylene chloride (20 mL,2 times), and the organic layers were combined and concentrated to dryness to give 14.1g (75% as 3-chloro-2-hydrazinopyridine) of the pure target product.
Example 14
This example provides a process for the preparation of ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate comprising the steps of:
(S1) adding 7g of sodium ethoxide (0.102 mol) and 100mL of ethanol to a reaction flask placed with mechanical stirring at 25 ℃ to obtain a reaction mixture;
(S2) after stirring and dissolving the reaction mixture obtained in the step (S1), 10g (0.070 mol) of 3-chloro-2-hydrazinopyridine is added into a reaction bottle in batches, after stirring for 25 minutes, 14.4g (0.084 mol) of diethyl maleate is added into the reaction mixture dropwise, stirring is continued for 1 hour at 25 ℃, then the reaction temperature is increased to 40 ℃ and stirring is continued for 2 hours, and then the reaction temperature is increased to 70 ℃ and stirring is continued for 3 hours, so that a reaction product is obtained;
(S3) placing the reaction product prepared in the step (S2) under ice bath, stirring for 20 minutes, then dropwise adding 7mL of glacial acetic acid, precipitating solid, concentrating the solid to dryness under the condition that the water bath is lower than 50 ℃, adding 10mL of water into the residue, fully stirring, and filtering to obtain a crude product;
(S4) the crude product obtained in the step (S3) was then dissolved in 50mL of methylene chloride, washed with 15mL of saturated brine, separated, the aqueous layer was extracted twice with methylene chloride (20 mL,2 times), and the organic layers were combined and concentrated to dryness to obtain 13.9g (74% as 3-chloro-2-hydrazinopyridine) of the pure target product.
Example 15
This example provides a process for the preparation of ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate comprising the steps of:
(S1) adding 7g of sodium ethoxide (0.102 mol) and 100mL of ethanol to a reaction flask placed with mechanical stirring at 25 ℃ to obtain a reaction mixture;
(S2) after stirring and dissolving the reaction mixture obtained in the step (S1), 10g (0.070 mol) of 3-chloro-2-hydrazinopyridine is added into a reaction bottle in batches, after stirring for 25 minutes, 14.4g (0.084 mol) of diethyl maleate is added into the reaction mixture dropwise, stirring is continued for 1 hour at 25 ℃, then the reaction temperature is increased to 40 ℃ and stirring is continued for 2 hours, and then the reaction temperature is increased to 70 ℃ and stirring is continued for 3 hours, so that a reaction product is obtained;
(S3) placing the reaction product prepared in the step (S2) under ice bath, stirring for 20 minutes, then dropwise adding 7mL of glacial acetic acid, precipitating solid, concentrating the solid to dryness under the condition that the water bath is lower than 50 ℃, adding 10mL of water into the residue, fully stirring, and filtering to obtain a crude product;
(S4) the crude product obtained in the step (S3) was then dissolved in 50mL of methylene chloride, washed with 20mL of saturated brine, separated, the aqueous layer was extracted twice with methylene chloride (20 mL,2 times), and the organic layers were combined and concentrated to dryness to obtain 13.1g (70% as 3-chloro-2-hydrazinopyridine) of the pure target product.
Example 16
This example provides a process for the preparation of ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate comprising the steps of:
(S1) adding 7g of sodium ethoxide (0.102 mol) and 100mL of ethanol to a reaction flask placed with mechanical stirring at 25 ℃ to obtain a reaction mixture;
(S2) after stirring and dissolving the reaction mixture obtained in the step (S1), 10g (0.070 mol) of 3-chloro-2-hydrazinopyridine is added into a reaction bottle in batches, after stirring for 25 minutes, 14.4g (0.084 mol) of diethyl maleate is added into the reaction mixture dropwise, stirring is continued for 1 hour at 25 ℃, and then the reaction temperature is increased to 40 ℃ and stirring is continued for 2 hours, so that a reaction product is obtained;
(S3) placing the reaction product prepared in the step (S2) under ice bath, stirring for 20 minutes, then dropwise adding 7mL of glacial acetic acid, precipitating solid, concentrating the solid to dryness under the condition that the water bath is lower than 50 ℃, adding 10mL of water into the residue, fully stirring, and filtering to obtain a crude product;
(S4) the crude product obtained in the step (S3) was then dissolved in 50mL of methylene chloride, washed with 20mL of saturated brine, separated, the aqueous layer was extracted twice with methylene chloride (20 mL,2 times), and the organic layers were combined and concentrated to dryness to give 9.4g (50% as 3-chloro-2-hydrazinopyridine) of the pure target product.
Example 17
This example provides a process for the preparation of ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate comprising the steps of:
(S1) adding 7g of sodium ethoxide (0.102 mol) and 100mL of ethanol to a reaction flask placed with mechanical stirring at 25 ℃ to obtain a reaction mixture;
(S2) after stirring and dissolving the reaction mixture obtained in the step (S1), 10g (0.070 mol) of 3-chloro-2-hydrazinopyridine is added into a reaction bottle in batches, after stirring for 25 minutes, 14.4g (0.084 mol) of diethyl maleate is added into the reaction mixture dropwise, stirring is continued for 1 hour at 25 ℃, and then the reaction temperature is increased to 40 ℃ and stirring is continued for 3 hours, so that a reaction product is obtained;
(S3) placing the reaction product prepared in the step (S2) under ice bath, stirring for 20 minutes, then dropwise adding 7mL of glacial acetic acid, precipitating solid, concentrating the solid to dryness under the condition that the water bath is lower than 50 ℃, adding 10mL of water into the residue, fully stirring, and filtering to obtain a crude product;
(S4) the crude product obtained in the step (S3) was then dissolved in 50mL of methylene chloride, washed with 20mL of saturated brine, separated, the aqueous layer was extracted twice with methylene chloride (20 mL,2 times), and the organic layers were combined and concentrated to dryness to give 11.6g (62% as 3-chloro-2-hydrazinopyridine) of the pure target product.
Example 18
This example provides a process for the preparation of ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate comprising the steps of:
(S1) adding 7g of sodium ethoxide (0.102 mol) and 100mL of ethanol to a reaction flask placed with mechanical stirring at 25 ℃ to obtain a reaction mixture;
(S2) after stirring and dissolving the reaction mixture obtained in the step (S1), 10g (0.070 mol) of 3-chloro-2-hydrazinopyridine is added into a reaction bottle in batches, after stirring for 25 minutes, 14.4g (0.084 mol) of diethyl maleate is added into the reaction mixture dropwise, stirring is continued for 1 hour at 25 ℃, then the reaction temperature is increased to 40 ℃ and stirring is continued for 2 hours, and then the reaction temperature is increased to 56 ℃ and stirring is continued for 3 hours, so that a reaction product is obtained;
(S3) placing the reaction product prepared in the step (S2) under ice bath, stirring for 20 minutes, then dropwise adding 7mL of glacial acetic acid, precipitating solid, concentrating the solid to dryness under the condition that the water bath is lower than 50 ℃, adding 10mL of water into the residue, fully stirring, and filtering to obtain a crude product;
(S4) the crude product obtained in the step (S3) was then dissolved in 50mL of methylene chloride, washed with 20mL of saturated brine, separated, the aqueous layer was extracted twice with methylene chloride (20 mL,2 times), and the organic layers were combined and concentrated to dryness to give 13.3g (71% as 3-chloro-2-hydrazinopyridine) of the pure target product.
The previous description of the embodiments is provided to facilitate a person of ordinary skill in the art in order to make and use the present invention. It will be apparent to those skilled in the art that various modifications can be readily made to these embodiments and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above-described embodiments, and those skilled in the art, based on the explanation of the present invention, should make improvements and modifications without departing from the scope of the present invention.
Claims (10)
1. A process for the preparation of ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate, comprising the steps of:
Dissolving 3-chloro-2-hydrazinopyridine in a solvent under alkaline condition, and then uniformly mixing with maleic diester to obtain a reactant, and performing post-treatment after the reaction to obtain 1- (3-chloropyridine-2-yl) -3-pyrazolone-5-carboxylic acid ethyl ester.
2. A process for the preparation of ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate according to claim 1, characterized in that sodium ethoxide is added to the solvent.
3. The method for preparing 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylic acid ethyl ester according to claim 2, wherein the solvent is ethanol.
4. The process for the preparation of 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylic acid ethyl ester according to claim 2, characterized in that the molar ratio of 3-chloro-2-hydrazinopyridine to sodium ethoxide is 1:1 to 1.3.
5. The process for preparing 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylic acid ethyl ester according to claim 4, wherein the molar ratio of 3-chloro-2-hydrazinopyridine to sodium ethoxide is 1:1.2.
6. The process for the preparation of 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylic acid ethyl ester according to claim 1, characterized in that the molar ratio of 3-chloro-2-hydrazinopyridine to maleic acid diester is 1:1.4 to 1.5.
7. The process for preparing 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylic acid ethyl ester according to claim 6, wherein the molar ratio of 3-chloro-2-hydrazinopyridine to maleic acid diester is 1:1.45.
8. The process for preparing ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate according to claim 1, wherein the reaction is carried out at a temperature of 20 to 70 ℃ for a period of 6 to 8 hours.
9. The method for preparing 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylic acid ethyl ester according to claim 1, wherein the reaction process is a stepwise temperature-rising reaction process comprising a first reaction process, a second reaction process and a third reaction process;
in the first reaction process, the temperature is 25 ℃ and the time is 1h;
In the second reaction process, the temperature is 40 ℃ and the time is 2 hours;
in the third reaction process, the temperature is 70 ℃ and the time is 3 hours.
10. The method for preparing 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylic acid ethyl ester according to claim 1, wherein the post-treatment is that after the reaction is finished, glacial acetic acid is dropwise added into the reaction product under ice bath to precipitate solid, and the solid is continuously concentrated under water bath condition to obtain concentrate; then dissolving the concentrate, and filtering to obtain a crude product;
The crude product was redissolved, washed with saturated brine, the aqueous layer was extracted with dichloromethane after extraction, the organic layers were combined,
Concentrating to obtain the ethyl 1- (3-chloropyridin-2-yl) -3-pyrazolidinone-5-carboxylate.
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