CN119431251A - A preparation method of 4-bromo-3,6-dichloropyridazine - Google Patents
A preparation method of 4-bromo-3,6-dichloropyridazine Download PDFInfo
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- CN119431251A CN119431251A CN202411491842.1A CN202411491842A CN119431251A CN 119431251 A CN119431251 A CN 119431251A CN 202411491842 A CN202411491842 A CN 202411491842A CN 119431251 A CN119431251 A CN 119431251A
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- dichloropyridazine
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- 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
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Abstract
The invention discloses a preparation method of 4-bromo-3, 6-dichloropyridazine, belonging to the field of organic synthesis. The method comprises the step of reacting a compound 1 serving as a substrate in the presence of a diazotizing agent, a bromine source and a solvent to obtain a compound 2, wherein the diazotizing agent is selected from any one or more of nitrous acid, nitrite or nitrous acid ester, and the bromine source is a mixture of copper bromide and cuprous bromide. The method can prepare 4-bromo-3, 6-dichloropyridazine with higher yield and higher purity.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of 4-bromo-3, 6-dichloropyridazine.
Background
The Sandmeyer reaction is a common reaction used to prepare halogenated aromatic hydrocarbons, which is currently widely recognized as a free radical reaction catalyzed by cuprous salts. However, there are some documents reporting that copper salts are also capable of catalyzing the Sandmeyer reaction on benzene rings and that the Sandmeyer reaction catalyzed by cuprous salts is not significantly different in yield.
However ,Efficient and Regioselective Halogenations of 2-Amino-1,3-thiazoles with Copper Salts(J.Org.Chem.2009,74,2578–2580) states that some aromatic rings are subject to significant differences in product and yield when catalyzed by copper and cuprous salts, respectively, and that cuprous salts are subject to significant Sandmeyer reactivity, whereas copper salts are substantially free of the corresponding product. Currently, no further investigation of the catalyst for the Sandmeyer reaction of the pyridazine ring has been made in the prior art.
Chinese patent CN 1146348118A discloses a compound having cancer therapeutic activity, 4-bromo-3, 6-dichloropyridazine being an important intermediate of the compound.
CN 116348118A also discloses a preparation method of 4-bromo-3, 6-dichloropyridazine, which uses cuprous bromide as bromine source and tert-butyl nitrite as diazotizing agent, and after the reaction, the target compound is separated by column chromatography, and the yield is 50.38%. This yield is quite disadvantageous in industrial production.
Disclosure of Invention
[ Technical problem ]
Provides a method for preparing 4-bromo-3, 6-dichloropyridazine with higher yield and lower impurity content.
Technical scheme
The invention provides a preparation method of 4-bromo-3, 6-dichloropyridazine, which has the following reaction formula:
The method comprises the following steps:
In the presence of diazotizing agent, bromine source and solvent, compound 1 is taken as substrate, compound 2 is obtained through reaction,
Wherein the diazotizing agent is selected from any one or more of nitrous acid, nitrite or nitrite,
The bromine source is a mixture of copper bromide and cuprous bromide.
In one embodiment of the invention, the molar ratio of cuprous bromide to cupric bromide is 1 (0.5-15), preferably 1 (0.5-12), specifically selected from 1:0.5, 1:1, 1:2, 1:9 or 1:12.
In one embodiment of the invention, the molar ratio of the diazotizing agent to the compound 1 is (1-2): 1, in particular optionally 1.5:1.
In one embodiment of the invention, the diazotizing agent is t-butyl nitrite.
In one embodiment of the invention, the molar ratio of the bromine source to the compound 1 is (1.0-1.8): 1, specifically alternatively 1.0:1, 1.3:1 or 1.5:1.
In one embodiment of the present invention, the solvent is selected from any one or more of acetonitrile, ethyl acetate, methyl acetate, formic acid, acetic acid, water, hydrochloric acid, DMSO.
In one embodiment of the invention, the mass to volume ratio of the compound 1 to the solvent is 1g (5-20) mL, specifically optionally 1:10.
In one embodiment of the invention, the reaction time is from 1 to 8 hours.
In one embodiment of the invention, the reaction temperature is 20-30 ℃.
In one embodiment of the invention, the preparation method of the 4-bromo-3, 6-dichloropyridazine specifically comprises the following reaction steps:
adding a solvent, a compound 1 and a bromine source into a reaction container at 20-30 ℃, dripping a diazotizing reagent, and stirring for reaction for 1-8h;
After the reaction is finished, the pH value of the system is regulated to 9-10, the solution is filtered, the filtrate is taken, the organic phase is taken, the water is washed until the pH value is 6-8, the solvent is removed, n-heptane is added for pulping, the filtering is carried out, the solid is taken, and the 4-bromo-3, 6-dichloropyridazine is obtained after drying.
In one embodiment of the invention, after the reaction is finished, the solvent is distilled off under reduced pressure, toluene is added, the pH value of the system is regulated to 9-10, the filtration is carried out, the filtrate is taken, the organic phase is taken, the water is washed to the pH value of 6-8, the solvent is removed, n-heptane is added for pulping, the filtration is carried out, the solid is taken, and the 4-bromo-3, 6-dichloropyridazine is obtained after drying.
Effects and effects of the invention
According to the preparation method of 4-bromo-3, 6-dichloropyridazine, the bromine source is a mixed bromine source of copper bromide and cuprous bromide, so that 4-bromo-3, 6-dichloropyridazine can be prepared with higher yield and higher purity.
Drawings
FIG. 1 is a HPLC chart of the reaction of sequence number 1 in example 1 of the present invention, wherein the target is at a retention time of 6.508min and impurity A is at a retention time of 3.648 min;
FIG. 2 is a HPLC chart of the reaction of sequence number 2 in example 1 of the present invention, wherein the target is at a retention time of 6.487min and impurity A is at a retention time of 3.638 min;
FIG. 3 is a HPLC chart of the reaction of sequence number 3 in example 1 of the present invention, wherein the target is at a retention time of 6.458 min;
FIG. 4 is a HPLC chart of the reaction of sequence number 4 in example 1 of the present invention, wherein the target is at a retention time of 6.460 min;
FIG. 5 is a HPLC chart of the reaction of sequence number 5 in example 1 of the present invention, wherein the target is at a retention time of 6.452 min;
FIG. 6 is a HPLC chart of the reaction of sequence number 6 in example 1 of the present invention, wherein the target is at a retention time of 6.449 min;
FIG. 7 is a HPLC chart of reaction No. 7 in example 1 of the present invention, wherein the target is at a retention time of 6.264 min;
FIG. 8 is an HPLC chromatogram of the product of example 2 of the present invention with a retention time of 6.295min as the target;
FIG. 9 is an HPLC chromatogram of the product of example 3 of the present invention, wherein the target is at a retention time of 6.246 min.
Detailed Description
In order to make the technical means, the creation features, the achievement of the purpose and the effect of the present invention easy to understand, the present invention is specifically described below with reference to the embodiments and the drawings.
In the examples below, each of the raw materials was a commercially available product unless otherwise specified.
In the following examples, commercial aqueous ammonia was a commercial aqueous solution containing 25% -28% ammonia, and was not titrated before use.
Example 1]
Preparation method of 4-bromo-3, 6-dichloropyridazine
In this example, bromine sources were screened as follows:
To the reaction vessel was added 20mL of acetonitrile, 2g of 4-amino-3, 6-dichloropyridazine (12.2 mmol,1.0 eq) and a bromine source (specific conditions are shown in Table 1) were sequentially added, the temperature was controlled at 20℃and after completion of dropwise addition of 1.89g of t-butyl nitrite (18.3 mmol,1.5 eq), the mixture was kept under stirring at 20℃for 3 hours, and the mixture was sampled and subjected to HPLC detection.
The screening results are shown in the following table.
TABLE 1 screening for bromine sources
| Sequence number | Copper bromide/eq | Cuprous bromide/eq | Reaction temperature | Yield of target product liquid phase |
| 1 | 1.5 | 0 | 20°C | 71.2% |
| 2 | 0 | 1.5 | 20°C | 45.4% |
| 3 | 0.5 | 1.0 | 20°C | 89.5% |
| 4 | 0.75 | 0.75 | 20°C | 90.3% |
| 5 | 1.0 | 0.5 | 20°C | 92.6% |
| 6 | 0.9 | 0.1 | 20°C | 94.8% |
| 7 | 1.2 | 0.1 | 20°C | 92.5% |
As shown in the above table and fig. 1-2, there is a significant impurity a (rt≡3.64 min) when copper bromide alone is used as the bromine source (fig. 1), whereas when copper bromide alone is used as the bromine source (fig. 2), a more significant impurity B (rt=5.11 min) is generated in addition to impurity a (rt≡3.64 min).
As shown in the above table and fig. 3-7, both impurity a and impurity B can be effectively suppressed and new impurities having a content of more than 10% are not newly generated when using a mixed bromine source of copper bromide and cuprous bromide.
Example 2 ]
Preparation method of 4-bromo-3, 6-dichloropyridazine
The embodiment provides a preparation method of 4-bromo-3, 6-dichloropyridazine, which comprises the following steps:
To the reaction vessel, 100mL of acetonitrile was added, 10g of 4-amino-3, 6-dichloropyridazine (61.0 mmol,1.0 eq), 12.3g of copper bromide (54.9 mmol,0.9 eq) and 0.88g of cuprous bromide (6.1 mmol,0.1 eq) were sequentially added, the temperature was controlled at 20℃and 9.44g of t-butyl nitrite (91.5 mmol,1.5 eq) were added dropwise, and after completion of the dropwise addition, the reaction was kept under stirring at 20℃for 4 hours.
The reaction solution was collected, the solvent was distilled off under reduced pressure, 50mL of toluene was added, the pH was adjusted to 9-10 using commercially available aqueous ammonia at room temperature, filtration was carried out, the filtrate was taken, the organic phase was taken and washed with water to pH 7, concentrated under reduced pressure, 10mL of n-heptane was added to pulp for 30min, filtration was carried out, and the solid was taken and dried to obtain 9.87g of 4-bromo-3, 6-dichloropyridazine in a yield of 71.0%. As shown in FIG. 8, the purity of 4-bromo-3, 6-dichloropyridazine prepared in this example was 98.7%.
Example 3 ]
Preparation method of 4-bromo-3, 6-dichloropyridazine
The embodiment provides a preparation method of 4-bromo-3, 6-dichloropyridazine, which comprises the following steps:
10L of acetonitrile was added to the autoclave, followed by 1kg of 4-amino-3, 6-dichloropyridazine (6.10 mol,1.0 eq), 1.63kg of copper bromide (7.32 mol,1.2 eq) and 87.5g of cuprous bromide (0.61 mol,0.1 eq), the temperature was controlled at 20℃and after completion of the dropwise addition of 943.5g of t-butyl nitrite (9.15 mol,1.5 eq), the mixture was stirred at 20℃for 2 hours.
The reaction solution was collected, pH was adjusted to 9-10 at room temperature using commercially available aqueous ammonia, filtered, the filtrate was taken, the organic phase was taken and washed with water to pH 7, concentrated under reduced pressure, slurried with 5L of n-heptane for 30min, filtered, the solid was taken, and dried to give 1.07kg of 4-bromo-3, 6-dichloropyridazine in a yield of 76.7%. As shown in FIG. 9, the purity of 4-bromo-3, 6-dichloropyridazine obtained in this example was 98.0%.
Effects and effects of the examples
According to the preparation method of 4-bromo-3, 6-dichloropyridazine related to the above embodiment, because the bromine source is a mixed bromine source of cupric bromide and cuprous bromide, the invention can prepare 4-bromo-3, 6-dichloropyridazine with higher yield under milder reaction conditions.
Further, as the molar ratio of the selected bromine source to the cuprous bromide to the cupric bromide is 1 (1-15), the liquid phase yield can reach more than 90 percent, the highest yield can reach 94.8 percent, and the separation yield can reach 76.7 percent.
Further, the above examples have developed a post-treatment method which can not only avoid column chromatography which is difficult to be applied industrially, but also effectively remove impurities to obtain a target product having a purity of 98% or more.
The above embodiments are preferred examples of the present invention, and are not intended to limit the scope of the present invention.
Claims (10)
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102884047A (en) * | 2009-12-04 | 2013-01-16 | 大正制药株式会社 | 2-pyridone compounds |
| US20130210769A1 (en) * | 2006-12-15 | 2013-08-15 | Irm Llc | Compounds and compositions as inhibitors of cannabinoid receptor 1 activity |
| WO2022052886A1 (en) * | 2020-09-08 | 2022-03-17 | 贝达药业股份有限公司 | Cd73 inhibitor and application thereof in medicine |
| WO2024213552A1 (en) * | 2023-04-12 | 2024-10-17 | F. Hoffmann-La Roche Ag | Nlrp3 inhibitors |
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- 2024-10-24 CN CN202411491842.1A patent/CN119431251A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130210769A1 (en) * | 2006-12-15 | 2013-08-15 | Irm Llc | Compounds and compositions as inhibitors of cannabinoid receptor 1 activity |
| CN102884047A (en) * | 2009-12-04 | 2013-01-16 | 大正制药株式会社 | 2-pyridone compounds |
| WO2022052886A1 (en) * | 2020-09-08 | 2022-03-17 | 贝达药业股份有限公司 | Cd73 inhibitor and application thereof in medicine |
| WO2024213552A1 (en) * | 2023-04-12 | 2024-10-17 | F. Hoffmann-La Roche Ag | Nlrp3 inhibitors |
Non-Patent Citations (1)
| Title |
|---|
| FABRICE G. SIMEON等: "Efficient and regioselective halogenations of 2-amino-1, 3-thiazoles with copper salts", 《JOURNAL OF ORGANIC CHEMISTRY》, vol. 74, 20 February 2009 (2009-02-20), pages 2578 - 2580 * |
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