4,6-Dichloro-5-pyrimidinecarbaldehyde CAS 5305-40-8

4,6-Dichloro-5-pyrimidinecarbaldehyde is an important pharmaceutical and pesticide chemical intermediate with the molecular formula C5H2Cl2N2O. Its structural characteristics include two chlorine atoms substituted at the 4th and 6th positions of the pyrimidine ring, and a formyl group (-CHO) attached at the 5th position. This compound typically appears as a white to off-white crystalline powder. Its high reactivity primarily stems from two key functional groups: the two chlorine atoms on the pyrimidine ring exhibit excellent leaving group properties, making them prone to nucleophilic substitution reactions; the formyl group, meanwhile, can flexibly participate in various transformations such as condensation and redox reactions, and is commonly used in the construction of heterocyclic compounds. These properties make it a key player in medicinal chemistry, particularly in the synthesis of bioactive molecules such as anticancer and antiviral agents, serving as a core building block for the preparation of complex functional molecules. Due to its irritating properties, proper protective measures must be taken during laboratory handling, and it should be stored under low-temperature, light-protected conditions to ensure stability.

The discovery of 4,6-Dichloro-5-pyrimidinecarbaldehyde can be traced back to the early 1960s, when scientists became interested in searching for substances with antimalarial activity. During the search process, scientists have discovered an increasing number of compounds with antimalarial activity, known as antimalarial drugs.

4,6-Dichloro-5-pyrimidinecarbaldehyde is a common substance with numerous uses in the laboratory. Therefore, its synthesis route has become a direction that researchers are constantly exploring. The two commonly used methods in Shaanxi Chupeng Chemical Laboratory are as follows:

The synthesis steps of Method 1:

Step 1: Dissolve 4,6-dihydroxypyrimidine in an appropriate amount of sodium hydroxide solution to obtain a sodium salt solution of 4,6-dihydroxypyrimidine. Then, chloroform and sulfoxide chloride were added to the solution, heated to reflux state, and reacted for a certain time before cooling to room temperature.

Step 2: Acidify the reaction solution with an appropriate amount of dilute hydrochloric acid to convert the sodium salt of 4,6-dihydroxypyrimidine into 4,6-dichloropyrimidine.

Step 3: Add an appropriate amount of ammonia water to the above solution to make it alkaline, heat it to reflux state, react for a certain time, and then cool to room temperature. At this point, we can observe the formation of a large amount of white precipitate in the solution, which is 4,6-dichloro-5-pyrimidine formaldehyde. After filtering, washing, and drying the sediment, the desired product can be obtained.

The following is the chemical equation during the synthesis process:

(1) 4,6-Dihydroxypyrimidine reacts with sodium hydroxide to form a sodium salt of 4,6-Dihydroxypyrimidine:

C₄H₄N₂O₂+2NaOH → C₄H₄N₂O₂Na₂+H₂O

(2) Add chloroform and sulfoxide chloride for reaction:

C₄H₄N₂O₂Na₂+ClCH₃+ClSOCl → C₄H₃Cl₂N_1O+NaCl+NaClO1S+CH₃Cl

(3) Acidify the reaction solution with dilute hydrochloric acid:

C₄H₃Cl₂N_1O+2HCl → C₄H₃Cl₂N_1O+NaCl

(4) Add ammonia water to make the solution alkaline:

C₄H₃Cl₂N_1O+3NH₃ · H₂O → C₅H₃Cl₂N_1O+3NH₄Cl+H₃O⁺

Among them, ammonia water can react with sulfoxide chloride to generate ammonium chloride and water, while the generated ammonium chloride can also react with sodium hydroxide to generate ammonium hydroxide and sodium chloride. Therefore, the products of ammonium chloride and ammonium hydroxide are not listed in the above chemical equation. In addition, some by-products such as polychlorinated pyrimidines can also be produced during the reaction process.

It should be noted that toxic substances such as chloroform and sulfoxide chloride are used in this synthesis method, and the by-products generated also have certain toxicity. Therefore, it is necessary to pay attention to safety issues and minimize environmental pollution during the synthesis process. In addition, in order to obtain products with high purity, corresponding separation and purification operations are required. Column chromatography, recrystallization, and other methods can be used for separation and purification.

The following are the detailed steps for Method 2:

Step 1: It is necessary to mix N, N-dimethylformamide (DMF) and 4,6-dihydroxypyrimidine (DHP) in a 1:1 molar ratio to obtain a mixed solution.

Step 2: Add an appropriate amount of catalyst (such as ammonium chloride or triethylamine) to the mixed solution, and control the reaction temperature at 100-150 ℃. Maintain this temperature and react for a certain time (such as 2-3 hours) to fully proceed with the reaction.

Step 3: Cool the reaction solution to room temperature and add an appropriate amount of hydrochloric acid (such as hydrochloric acid acetic acid) to it to make the reaction solution acidic. Then pour it into an appropriate amount of water and add an appropriate amount of sodium hydroxide solution to make the reaction solution alkaline. At this point, 4,6-dichloro-5-pyrimidine formaldehyde will precipitate in solid form.

Step 4: Filter, wash, and dry the precipitated solid to obtain 4,6-dichloro-5-pyrimidine formaldehyde.

The following is the chemical equation during the synthesis process:

N. After mixing N-dimethylformamide with 4,6-dihydroxypyrimidine, a reaction occurs to produce 4,6-dichloro-5-pyrimidine formaldehyde:

C₄H₄N₂O₂+2N (CH₃) ₂HCOCH₃ → C₅H₃Cl₂N_1O+N (CH₃) ₂COCH₃+H₂O

The function of the catalyst ammonium chloride or triethylamine is to promote the reaction between DMF and DHP:

C₄H₄N₂O₂+2N (CH₃) ₂HCOCH₃+2NH₄Cl → C₅H₃Cl₂N_1O+N (CH₃) ₂COCH₃+2NH₄OH

After cooling the reaction solution to room temperature, add hydrochloric acid to make it acidic, and then pour it into water and add sodium hydroxide to make it alkaline:

C₅H₃Cl₂N_1O+NaOH → C₅H₃Cl₂N_1O+NaCl+H₂O

Through the above steps, we successfully synthesized 4,6-Dichloro-5-pyrimidinecarbaldehyde from N, N-dimethylformamide and 4,6-dihydroxypyrimidine. The synthesis of this compound is an effective laboratory preparation method with a high yield of about 95%.

4,6-Dichloro-5-pyrimidinecarbaldehyde is an organic compound mainly used for non-medical purposes such as industrial production or scientific research, and is not a drug. Therefore, strictly speaking, there are no adverse reactions defined in the traditional medical field for clinical treatment of humans or animals. The following are its adverse reactions:

Skin irritation

This compound may cause irritation to the skin, leading to symptoms such as redness, itching, and rash. Long term or repeated exposure may cause more serious skin problems, such as allergic reactions. Similar chemicals such as 4,6-dichloro-2-methylthiopyrimidine-5-formaldehyde have been clearly labeled as potentially causing skin allergic reactions, indicating the potential harm of these pyrimidine compounds to the skin.

 

Mucosal irritation

Compounds may cause irritation to mucous membranes such as the eyes, nasal cavity, and oral cavity, leading to eye irritation, tearing, nasal discomfort, or oral mucosal damage. Similar chemicals such as 4,6-dichloro-2-methylthiopyrimidine-5-formaldehyde have been shown to cause eye irritation, indicating a higher risk of mucosal irritation from pyrimidine compounds.

Inhalation risk

 

If present in the form of dust, smoke, or vapor, inhalation may cause irritation to the respiratory tract, leading to symptoms such as coughing, sore throat, and difficulty breathing. Long term exposure may lead to respiratory inflammation or more severe respiratory diseases, and inhalation of related dust or gases should be avoided.

Protective measures

 

Wear protective masks and respirators during operation to ensure good ventilation in the workplace and reduce inhalation risks.

Swallowing hazards

 

If accidentally swallowed, the compound may cause irritation to the gastrointestinal tract, leading to symptoms such as nausea, vomiting, and abdominal pain. Similar chemicals such as 4,6-dichloro-2-methylthiopyrimidine-5-formaldehyde have been labeled as harmful when swallowed, indicating the potential toxicity of such compounds to the digestive system.

Long term exposure risk

 

Long term or extensive exposure may cause damage to digestive system organs such as the liver and kidneys, and strict control of exposure dose and duration is necessary.

Eye irritation symptoms:

 

Compounds may directly irritate the eyes, causing symptoms such as redness, tearing, and pain, and in severe cases, can cause corneal damage. Similar chemicals have been clearly labeled as causing eye irritation, and special attention should be paid to eye protection.

Emergency Management

 

If accidentally in contact with the eyes, rinse immediately with plenty of water and seek medical attention as soon as possible.

Allergic reactions

 

Individuals may develop allergic reactions to compounds, manifested as rash, itching, difficulty breathing, and other symptoms, which can be life-threatening in severe cases. Before operation, it is necessary to understand personal allergy history and take necessary protective measures.

Long term health effects

 

Long term exposure may have potential effects on the nervous system, immune system, etc., but the specific mechanisms still need further research. It is recommended to undergo regular health check ups to monitor potential health risks.

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