Lamivudine

 Lamivudine (CAS NO.134678-17-4) was produce by Bernard Belleau while at work at Nghe Nguyen-Ga and McGill University at the Montreal-based IAF BioChem International, Inc. laboratories in 1989. Initially designed as an antiviral agent, the drug's effectiveness for treating HIV in combination with AZT was discovered by Yung-Chi (Tommy) Cheng at Yale University. The drug was later licensed to the British pharmaceutical company Glaxo for a 14 percent royalty.
 Lamivudine (CAS NO.134678-17-4) was approved by the Food and Drug Administration (FDA) on November 17, 1995 for use with zidovudine (AZT) and again in 2002 as a once-a-day dosed medication. The fifth antiretroviral drug on the market, it was the last NRTI for three years while the approval process switched to protease inhibitors. According to the manufacturer's 2004 annual report, its patent will expireand in Europe in 2011 and in the United States in 2010 .

APPEARANCE: White to off-white crystalline powder
ASSAY: 98.0 - 102.0%
RESIDUE ON IGNITION: 0.25% max
LOSS ON DRYING: 0.5% max
OPTICAL ROTATION: -93^° ~ -100^°
HEAVY METALS: 20 ppm max

1. Introduction of Lamivudine
Lamivudine (CAS NO.134678-17-4) is a white crystalline powder. The IUPAC Name of this chemical is 4-amino-1-[(2S,5R)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one. Lamivudine belongs to Active Pharmaceutical Ingredients;Antivirals for Research and Experimental Use;Biochemistry;Chemical Reagents for Pharmacology Research;Nucleosides and their analogs;Nucleosides, Nucleotides & Related Reagents;Anti-virals;Intermediates & Fine Chemicals;Pharmaceuticals;API's.

Its Classification Code is Anti-HIV agents; Anti-Infective Agents; Anti-Retroviral Agents; Antiviral; Antiviral Agents; Enzyme Inhibitors; Nucleic Acid Synthesis Inhibitors; Reverse transcriptase inhibitors. Lamivudine is soluble in water, sparingly soluble in methanol and slightly soluble in ethanol.

2. Properties of Lamivudine
Physical properties about Lamivudine are:
(1)Index of Refraction: 1.754; (2)Molar Refractivity: 54.14 cm³; (3)Molar Volume: 132.2 cm³; (4)Polarizability: 21.46×10^-24 cm³; (5)Surface Tension: 79.3 dyne/cm; (6)Density: 1.73 g/cm³; (7)Flash Point: 241.3 °C; (8)Enthalpy of Vaporization: 85.17 kJ/mol; (9)Melting Point: 177 °C; (10)Boiling Point: 475.4 °C at 760 mmHg; (11)Vapour Pressure: 4.91E-11 mmHg at 25°C; (12)XLogP3: -0.9; (13)H-Bond Donor: 2; (14)H-Bond Acceptor: 4.

3. Structure Descriptors of Lamivudine
(1)Canonical SMILES: C1C(OC(S1)CO)N2C=CC(=NC2=O)N
(2)Isomeric SMILES: C1[C@@H](O[C@@H](S1)CO)N2C=CC(=NC2=O)N
(3)InChI: InChI=1S/C8H11N3O3S/c9-5-1-2-11(8(13)10-5)6-4-15-7(3-12)14-6/h1-2,6-7,12H,3-4H2,(H2,9,10,13)/t6-,7+/m1/s1
(4)InChIKey: JTEGQNOMFQHVDC-RQJHMYQMSA-N
(5)Smiles: c1cn(c(=O)nc1N)[C@@H]2CS[C@@H](O2)CO

4. Toxicity of Lamivudine
Oral Toxicity: Not expected to be toxic following ingestion.
Inhalation Toxicity: No studies have been conducted.

5. Safety information of Lamivudine
RTECS: UW7361333
Hazardous Substances Data: 134678-17-4(Hazardous Substances Data)

6. Uses of Lamivudine
Lamivudine has been used for treatment of chronic hepatitis B at a lower dose than for treatment of HIV. It improves the seroconversion of e-antigen positive hepatitis B and also improves histology staging of the liver. Long term use of lamivudine unfortunately leads to emergence of a resistant hepatitis B virus (YMDD) mutant. Despite this, lamivudine is still used widely as it is well tolerated. Lamivudine is a reverse transcriptase inhibitor and antiviral.

7. Production of Lamivudine
Selective 6-O-sulfonylation reaction of compound (I), followed by acetylation to give the compound (II) in 96.7% yield. The compound (II) in acetic acid as solvent, and 3 mol of hydrogen bromide / L acid (45%, w / v) reaction, brominated to give the compound (III), in 99% yield. Bromide (III) and 3.3moI. Xanthan ethyl potassium, in acetone under reflux, thio and cyclization; then subjected to hydrolysis with ammonia in methanol, to obtain the compound (IV), two step yield 72%. Compound (IV) was purified by column chromatography, as a crystalline solid. Compound (IV) with 1.4 moles of sodium periodate treatment, ring-opening to give a 2,3 - cis-diol; the formation of an aldehyde followed by reduction with sodium borohydride, and formed in the form of a ketal to protect the diol to give compound (V), 60% yield. The compound (V) silylation to protect the rest of the primary alcohol, and then stripped of the ketal to give the compound (VI), 63% yield. Lead tetraacetate to the diol compound (VI) oxide, and then to the Shop two pyridinium salt to further oxidation, to obtain compound (VII), this oxidation method does not affect the sulfur. The compound (VII) and then oxidation of the lead tetraacetate, to obtain the compound (VIII), in 66% yield [meter] with the compound (VI). The compound (VIII) and (IX), in dichloroethane, TMSOTf as Lewis acid catalyst, obtained by condensation of the compound (X), a 64% yield. Isomer thereof, in addition to the compound (X) at half the amount of the compound (X), they can be used silica gel chromatography to separate. The compound (X) with ammonia - methanol come acetyl, 73% yield; then tetra-n-butylammonium fluoride to de-silylation, i.e. to obtain naphthalene, 75% yield.



Or it can be got from Acetoxy-2-(diphenyl-t-butylsilyl-oxymethyl)-1,3-oxathiolane and 4-acetyl amino-2-trimethylsilyloxy pyrimidine dissolved in dichloroethane under the condensation of catalyzed Lewis acid.