CN112645883B - Preparation method of 3,6-dichloropyridazine - Google Patents
Preparation method of 3,6-dichloropyridazine Download PDFInfo
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- CN112645883B CN112645883B CN202011537250.0A CN202011537250A CN112645883B CN 112645883 B CN112645883 B CN 112645883B CN 202011537250 A CN202011537250 A CN 202011537250A CN 112645883 B CN112645883 B CN 112645883B
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- dichloropyridazine
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- dihydroxypyridazine
- chlorosuccinimide
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- GUSWJGOYDXFJSI-UHFFFAOYSA-N 3,6-dichloropyridazine Chemical compound ClC1=CC=C(Cl)N=N1 GUSWJGOYDXFJSI-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims abstract description 76
- BGRDGMRNKXEXQD-UHFFFAOYSA-N Maleic hydrazide Chemical compound OC1=CC=C(O)N=N1 BGRDGMRNKXEXQD-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 12
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- 238000006243 chemical reaction Methods 0.000 claims description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- 239000012065 filter cake Substances 0.000 claims description 11
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 238000000967 suction filtration Methods 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 3
- 239000012320 chlorinating reagent Substances 0.000 abstract description 5
- 238000003912 environmental pollution Methods 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 14
- 239000012535 impurity Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 7
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 5
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 238000002386 leaching Methods 0.000 description 3
- 229960002317 succinimide Drugs 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000036632 reaction speed Effects 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 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 1
- DTXVKPOKPFWSFF-UHFFFAOYSA-N 3(S)-hydroxy-13-cis-eicosenoyl-CoA Chemical compound NC1=CC=C(Cl)N=N1 DTXVKPOKPFWSFF-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 231100000481 chemical toxicant Toxicity 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000007337 electrophilic addition reaction Methods 0.000 description 1
- 238000007336 electrophilic substitution reaction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 150000008301 phosphite esters Chemical class 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having 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
- C07D237/12—Halogen atoms or nitro radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of 3,6-dichloropyridazine, which comprises the following steps: 5363 the production of 3,6-dichloropyridazine by chlorination of 3,6-dihydroxypyridazine and N-chlorosuccinimide; the chlorination reaction route is as follows:
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a preparation method of 3,6-dichloropyridazine.
Background
3,6-dichloropyridazine is an important pharmaceutical intermediate, published in Guangzhou chemical journal, vol.40, no. 9, 5.2012, xin Lei, et al: in the research of microwave synthesis of 3-amino-6-chloropyridazine, a preparation method of 3,6-dichloropyridazine is disclosed, which comprises the following steps:
(1) 8978 Synthesis of zxft 8978-dihydroxypyridazine:
a500 ml three-necked flask was charged with 72.5ml of hydrazine hydrate (80%) (1.3 mol), 120ml of 30% hydrochloric acid was added dropwise, 98g of maleic anhydride (1 mol) was added thereto, and the mixture was refluxed at 110 ℃ for 3 hours. Cooling, crystallizing, suction filtering to obtain yellow-white solid, washing the filter cake with cold ethanol 3-4 times, collecting white solid 3,6-dihydroxypyridazine 100g, yield 91%, m.p. 298-300 deg.C.
(2) Synthesis of 3,6-dichloropyridazine:
22g of 3, 6-dihydroxypyridazine (0.2 mol) and 232.8g of phosphorus pentachloride (1.12 mol) were charged in a three-necked flask, and heated to 125 ℃ for reaction for 4 hours. The generated phosphorus oxychloride is evaporated under reduced pressure, the obtained product is cooled to room temperature, and the coffee viscous liquid remained in the three-neck flask is poured into water for quenching. 28% ammonia water is added dropwise to adjust the pH value to about 8. The brown solid was suction filtered, the filtrate was extracted with dichloromethane, dried over anhydrous sodium sulfate, the dichloromethane was distilled off to give a solid, and the solids were combined. Recrystallizing with n-hexane to obtain white 3,6-dichloropyridazine crystal 24.4g, yield 82%, melting point m.p.67-69 deg.C.
The traditional process for preparing 3,6-dichloropyridazine needs to use a chlorinating agent which is usually phosphorus oxychloride, thionyl chloride, chlorine, phosphorus trichloride or phosphorus pentachloride, and has the following problems:
firstly, the use of phosphorus oxychloride, thionyl chloride, chlorine, phosphorus trichloride or phosphorus pentachloride inevitably results in the generation of hydrogen chloride, which causes serious environmental pollution.
Secondly, phosphorus oxychloride, thionyl chloride, chlorine, phosphorus trichloride or phosphorus pentachloride, highly toxic chemicals, the reaction temperature is high, and the process risk is high.
Thirdly, phosphorus oxychloride is used, a large amount of toluene or dichloromethane is needed for extracting products, the environmental pollution is large, and the cost is high.
Fourthly, the reaction of 3,6-dihydroxypyridazine to 3,6-dichloropyridazine through chlorination belongs to substitution reaction of hydroxyl, phosphorus trichloride generally used in the reaction of substitution of hydroxyl by chlorine atoms is easy to generate side reaction of phosphite ester, and phosphorus pentachloride can generate a large amount of side by-product phosphorus oxychloride; the NCS used in the invention is a more convenient electrophilic addition and electrophilic substitution reagent, has less process impurities, safer and simpler process operation and is more environment-friendly.
Disclosure of Invention
The invention aims to provide a preparation method of 3,6-dichloropyridazine, which solves the technical problems of large environmental pollution, large process risk and high cost of the conventional preparation method of 3,6-dichloropyridazine by adopting a traditional chlorinating agent.
In order to solve the technical problems, the invention adopts the following technical scheme that the preparation method of 3,6-dichloropyridazine is characterized by comprising the following steps: 3,6-dihydroxypyridazine and N-chlorosuccinimide are subjected to chlorination reaction to generate 3,6-dichloropyridazine;
the reaction route is as follows:
by adopting the technical scheme, the method has the following beneficial effects: the invention selects the N-chlorosuccinimide NCS to replace phosphorus oxychloride as the raw material, the production process is safer and more efficient, and the operation is safer and more environment-friendly.
In order to solve the technical problem of how to specifically prepare 3,6-dichloropyridazine, the invention adopts the following technical scheme, and the preparation method of 3,6-dichloropyridazine comprises the following steps:
(1) Ethanol, 3,6-dihydroxypyridazine and hydrochloric acid in a reaction vessel; heating and stirring;
(2) And continuously adding N-chlorosuccinimide NCS into the reaction vessel, controlling the temperature to react, cooling and crystallizing, and filtering to obtain a filter cake, namely 3,6-dichloropyridazine.
By adopting the technical scheme, the method has the following beneficial effects:
(1) The invention prepares 3,6-dichloropyridazine from N-chlorosuccinimide NCS and 3,6-dihydroxypyridazine, the process has simple steps and simple operation, and the by-product succinimide in the process can be recovered by distilling and recovering ethanol. Less environmental pollution and higher product purity, and is more beneficial to industrial production.
(2) The N-chlorosuccinimide NCS is adopted as a chlorinating agent, so that the character is stable and the toxicity is low.
(3) The N-chlorosuccinimide NCS is adopted as a chlorinating agent, the chlorination reaction condition is mild, the product extraction is simple, and only suction filtration or centrifugation is needed.
(4) The product produced by crystallization by the preparation method has good product quality, and the product yield is more than 89.8 percent and reaches 92.6 percent at most; the purity of the product is over 99.3 percent and reaches 99.5 percent at most.
In order to solve the technical problem that 3,6-dihydroxypyridazine is completely reacted incompletely, the invention adopts the following technical scheme that the molar ratio of 3,6-dihydroxypyridazine to N-chlorosuccinimide NCS is 1: (2.05-2.1), the slight excess of NCS can make 3,6-dihydroxypyridazine completely react, and simultaneously, the waste of NCS is avoided.
In order to solve the technical problems of more impurities and low yield of the existing preparation method, the invention adopts the following technical scheme that the weight ratio of 3,6-dihydroxypyridazine to ethanol is 1: (2-4), not only can ensure that the main impurity succinimide is completely dissolved, but also can ensure that the product is dissolved in the main impurity succinimide as little as possible.
In order to solve the technical problem of poor process safety of the existing preparation method, the invention adopts the following technical scheme that the weight ratio of 3,6-dihydroxypyridazine to hydrochloric acid is 1: (0.09-0.11) can sufficiently promote the reaction to be stably carried out, and unsafe phenomena such as material aggregation, rapid temperature rise and the like are avoided.
In order to solve the technical problem of poor process safety of the existing preparation method, the invention adopts the following technical scheme that when the N-chlorosuccinimide NCS is added, the temperature is controlled to be 40-45 ℃, and unsafe factors caused by over-high reaction rate and over-high heat release can be effectively avoided.
In order to solve the technical problems of more impurities and lower yield of the existing preparation method, the invention adopts the following technical scheme that the reaction temperature in the step (2) is not more than 60 ℃ and the time is 1-3 hours, so that the impurity increase caused by overhigh temperature can be effectively avoided, and the impurity increase caused by incomplete reaction and overlong reaction time can be effectively avoided by controlling the reaction time.
In order to solve the technical problems of more impurities and lower yield of the existing preparation method, the invention adopts the following technical scheme that the crystallization temperature is 5-10 ℃, the crystallization time is 1-3 hours, so that the product can be fully crystallized, and the separation of impurities is avoided.
In order to solve the technical problem of more impurities in the existing preparation method, the invention adopts the following technical scheme that the drying mode of the filter cake is vacuum drying, the vacuum drying temperature is 40-50 ℃, the vacuum degree is-0.08 MPa to-0.1 MPa, and the vacuum drying time is 3-5 hours.
In order to solve the technical problem that the reaction speed of the N-chlorosuccinimide is too high, the invention adopts the following technical scheme that the N-chlorosuccinimide is put into a reaction vessel in 3-5 batches, the weight of each batch is equivalent, the difference is not too large, the reaction speed is effectively prevented from being too high, and the reaction is ensured to be complete.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1:
27g of ethanol is added into a 250ml reaction bottle, and stirring is started; adding 3,6-dihydroxypyridazine 9g and hydrochloric acid 0.9g; heating to 40 ℃; adding 22.4g NCS (N-chlorosuccinimide) into a reaction bottle for 3 times, wherein the temperature of the NCS is 40-45 ℃ every time, and the temperature is not more than 60 ℃ in the reaction process; after the NCS feeding is finished, controlling the temperature to be 45-55 ℃ and reacting for 2 hours; cooling the reaction liquid to 5-10 ℃, then starting timing crystallization for 2 hours, carrying out suction filtration, and leaching a filter cake with a small amount of absolute ethyl alcohol; the filter cake is dried for 4 hours in vacuum at 40-50 ℃ and the vacuum degree of minus 0.09 MPa; 10.7g of a white solid was obtained, the calculated yield was 89.8%, the purity (99.3%), the melting point was 68.2-68.7 ℃ (document 68-69 ℃).
Example 2:
adding 180g of ethanol into a 5L reaction bottle, and starting stirring; then 3,6-dihydroxypyridazine 90g and hydrochloric acid 9g are put in; heating to 40 ℃; adding 222.1g of NCS (N-chlorosuccinimide) into a reaction bottle for 5 times, wherein the temperature of the NCS is 40-45 ℃ every time, and the temperature is not more than 60 ℃ in the reaction process; after the NCS feeding is finished, controlling the temperature to be 45-55 ℃ and reacting for 2 hours; cooling the reaction liquid to 5-10 ℃, then starting timing crystallization for 2 hours, carrying out suction filtration, and leaching a filter cake with a small amount of absolute ethyl alcohol; vacuum drying the filter cake for 4 hours at 40-50 ℃ under the vacuum degree of-0.09 MPa; 110.4g of white solid is obtained, the calculated yield is 92.6%, the purity is 99.5%, and the melting point is 68.2-68.8 ℃ (68-69 ℃ in the literature).
Example 3:
adding 7.2kg of ethanol into a 10L reaction bottle, and starting stirring; then 3,6-dihydroxypyridazine 1.8kg and hydrochloric acid 180g are added; heating to 40 ℃; adding 4.40kg of NCS (N-chlorosuccinimide) into a reaction bottle for 5 times, wherein the temperature of the NCS is 40-45 ℃ every time, and the temperature is not more than 60 ℃ in the reaction process; after the NCS feeding is finished, controlling the temperature to be 45-55 ℃ and reacting for 2 hours; cooling the reaction liquid to 5-10 ℃, then starting timing crystallization for 2 hours, carrying out suction filtration, and leaching a filter cake with a small amount of absolute ethyl alcohol; the filter cake is dried for 4 hours in vacuum at 40-50 ℃ and the vacuum degree of minus 0.09 MPa; 2.18kg of a white solid was obtained, and the calculated yield was 91.0%, the purity (99.4%), and the melting point was 68.3 to 68.7 ℃ (document 68 to 69 ℃).
Claims (6)
1. A preparation method of 3,6-dichloropyridazine is characterized by comprising the following steps: 3,6-dihydroxypyridazine and N-chlorosuccinimide are subjected to chlorination reaction to generate 3,6-dichloropyridazine;
the preparation method comprises the following steps:
(1) Adding ethanol, 3,6-dihydroxypyridazine and hydrochloric acid into a reaction container, and heating and stirring; the weight ratio of 3,6-dihydroxypyridazine to ethanol is 1: (2-4); the weight ratio of 3,6-dihydroxypyridazine to hydrochloric acid is 1: (0.09-0.11);
(2) Continuously adding N-chlorosuccinimide into the reaction container, carrying out chlorination reaction, cooling and crystallizing, and carrying out suction filtration to obtain a filter cake, namely 3,6-dichloropyridazine; the mole ratio of 3,6-dihydroxypyridazine to N-chlorosuccinimide is 1: (2.05-2.1);
the chlorination reaction route is as follows:
2. the method for preparing 3,6-dichloropyridazine according to claim 1, wherein the temperature for continuously adding N-chlorosuccinimide into the reaction vessel is controlled to be 40-45 ℃.
3. The process for preparing 3,6-dichloropyridazine according to claim 1, wherein the chlorination reaction temperature in step (2) is not more than 60 ℃ and the chlorination reaction time is 1-3 hours.
4. The process for preparing 3,6-dichloropyridazine according to claim 1, wherein the crystallization temperature is 5 to 10 ℃ and the crystallization time is 1 to 3 hours.
5. The preparation method of 3,6-dichloropyridazine according to claim 1, wherein the filter cake is vacuum dried at 40-50 ℃ under a vacuum degree of-0.08 MPa-0.1 MPa for 3-5 hours.
6. The method for preparing 3,6-dichloropyridazine according to claim 1, wherein the N-chlorosuccinimide is added to the reaction vessel in 3 to 5 portions.
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Address after: 225200 No.86 Shuangshu Road, Xiannv Town, Jiangdu District, Yangzhou City, Jiangsu Province Patentee after: Tianhe Pharmaceutical Co.,Ltd. Country or region after: China Address before: 225200 No.86 Shuangshu Road, Xiannv Town, Jiangdu District, Yangzhou City, Jiangsu Province Patentee before: Tianhe Pharmaceutical Co.,Ltd. Country or region before: China |
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