4-Aminopyrimidine (CAS No. 591-54-8) – Technical Analysis and Industrial Applications of a Core Pyrimidine Intermediate

I. Basic Information and Physicochemical Properties

1. Basic Chemical Information

• English Name: 4-Aminopyrimidine

• CAS No.: 591-54-8

• Molecular Formula: $C_4{H}_5{N}_3$

• Molecular Weight: 95.10

• Appearance: White to off-white crystalline powder, odorless, bitter taste.

2. Physicochemical Properties

• Basicity: The amino group (-NH?) exhibits weak basicity (pKa ≈ 4.8) and forms salts with HCl, H?SO?, etc. (e.g., 4-aminopyrimidine hydrochloride).

• Reactivity: The amino group at position 4 undergoes acylation and alkylation; nitrogen atoms in the pyrimidine ring participate in coordination chemistry.

• Stability: Stable at room temperature; decomposes under high heat or strong acidity.

• Slightly soluble in cold water (1.2 g/100 mL, 25°C).

• Freely soluble in hot water, methanol, ethanol, and dilute acids; soluble in pyridine; insoluble in ether.

• Melting Point: 200–202°C (decomposes)

• Boiling Point: 341°C (atmospheric pressure)

• Density: 1.32 g/cm3

• Solubility:

• Chemical Characteristics:

II. Upstream and Downstream Industrial Chain Analysis

1. Upstream Raw Materials and Synthesis Process

• 4-Hydroxypyrimidine (CAS: 4895-89-2)

• Ammonia solution (NH?·H?O) or liquid ammonia.

• Core Raw Materials:

• Mainstream Synthesis Route:
  Ammonolysis Method:
  4-Hydroxypyrimidine reacts with excess ammonia in a high-pressure reactor, catalyzed by copper salts (e.g., CuCl?), at 180–200°C and 5–8 MPa for 12–16 hours. After acidification, neutralization, and crystallization, 4-aminopyrimidine with ≥99% purity is obtained (yield: 75–80%).
  Reaction Equation:
  $C_4{H}_4{N}_{2}O+N{H}_3\underset{\text{high temp, pressure}}{\overset{\text{catalyst}}{\to }}{C}_4{H}_5{N}_3+H_{2}O$

2. Downstream Products and Derivatives

• Ligand for metal-organic frameworks (MOFs).

• Synthesis of fluorescent probes and biodetection reagents (e.g., DNA base analogs).

• Synthesis of pyrimidine-based fungicides (e.g., cyprodinil, pyrimethanil), herbicides (e.g., orthosulfamuron).

• Production of insect growth regulators (e.g., chitin synthesis inhibitor intermediates).

• Synthesis of antimalarials (e.g., pyrimethamine), antivirals (e.g., lamivudine precursors), anticancer drugs (e.g., pyrimidine-based DNA synthesis inhibitors).

• Production of novel immunomodulators (e.g., JAK kinase inhibitor intermediates).

• Pharmaceutical Intermediates:

• Pesticide Intermediates:

• Materials and Fine Chemicals:

III. Core Application Fields

1. Pharmaceutical R&D and Drug Synthesis

• Antimalarial Key Intermediate:
  Condensation with 2,4-dichlorobenzaldehyde yields pyrimethamine, a frontline antimalarial drug that inhibits Plasmodium dihydrofolate reductase, blocking nucleic acid synthesis.

• Antiviral Drug Precursor:
  Reacts with ribonucleosides to produce nucleoside analogs (e.g., lamivudine intermediates) for anti-HIV/HBV drugs, competitively inhibiting viral reverse transcriptase.

• Anticancer Drug Synthesis:
  Serves as a pyrimidine ring scaffold in 5-fluorouracil (5-FU) derivatives, interfering with DNA replication to inhibit tumor cell proliferation (used in breast and gastrointestinal cancers).

2. Pesticide Innovation and Plant Protection

• High-Efficiency Fungicide Intermediate:
  Reacts with cyclohexanone to form cyprodinil, effective against Botrytis cinerea and Venturia inaequalis (efficacy >90%), with systemic and curative actions.

• Sulfonylurea Herbicide Key Raw Material:
  Condenses with sulfonamides to produce orthosulfamuron, selectively controlling annual weeds in rice fields with crop safety.

3. Materials Science and Fine Chemicals

• MOFs Ligand:
  Nitrogen atoms coordinate with metal ions (e.g., Zn2?, Cu2?) to form high-surface-area MOFs for gas adsorption (e.g., CO? capture) and catalysis.

• Biodetection Reagents:
  Modified with fluorophores (e.g., FITC) to create base analog probes for DNA/RNA sequence-specific detection (nanomolar sensitivity).

IV. Technical Advantages and Market Dynamics

• Technical Barriers:
  High-pressure ammonolysis requires precise control of catalyst dosage and temperature. Continuous flow reactors reduce reaction time to 4 hours, increasing yield to >85%.

• Production Capacity:
  Global annual capacity ≈150 tons (China: 60%), mainly produced by Jiangsu Lianhua Technology, Shandong Yu’ang Chemical, etc., via ammonolysis.

• Market Demand:
  Driven by antimalarials, novel pesticides, and innovative drug R&D, demand grew 18% YoY in 2024. The 2025 market is projected to exceed CNY 30 million, with pharmaceuticals accounting for 65%.

V. Safety and Storage Recommendations

• Hazards:
  Inhalation of dust may cause respiratory irritation; skin contact requires immediate washing. Rat oral LD50 >2000 mg/kg (low toxicity).

• Storage Conditions:
  Store in airtight containers in a cool, dry place (≤25°C), protected from light, moisture, oxidants, and strong acids. Recommended packaging: polyethylene bags or cardboard drums.