Pregabalin is a white crystalline solid, usually in the form of colorless or almost colorless granules or powder. The chemical name for is (3S)-3-{[(2S)-1-(methyl)ethyl]amino}propanoic acid. Its molecular formula is C8H17NO2, CAS 148553-50-8, and its molecular weight is 159.23 g/mol. It is a chiral compound with one chiral center. It has high solubility in water and can be dissolved quickly. It also has good solubility in other solvents, including methanol, ethanol, and dimethyl sulfoxide. The pH is low (acidic), generally between 2-3. It is relatively stable at room temperature and is not easy to decompose or degrade. However, it may be sensitive to strong oxidizing agents and light. Precise assay methods usually include high-performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS), which enable their quantitative analysis and identification.
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Pregabalin (pragueline hydrochloride) is an antiepileptic and analgesic drug. Several synthetic methods of Pregabalin will be introduced.
1. Rosenmund-Von Braun reaction method:
a. Step 1: First, 3-aminopropionitrile is reduced to 3-aminopropanol by hydrogenation.
Reaction formula: HCN + 2H2 → H2C=CH2 + NH3
b. Step 2: react 3-aminopropanol with ethylene oxide to generate the corresponding esterification product.
Reaction formula: H2C=CH2 + CH2O → CH3CHOCH2CH2OH
c. Step 3: Under acidic conditions, react the ester with glycidone to form Pregabalin.
Reaction formula: CH3CHOCH2CH2OH + CH3COCH2O → (CH3)2CHNCOCH2CH2OC(O)CH3
d. Step 4: Finally, pregabalin is converted to hydrochloride form by hydrochloric acid treatment.
Reaction formula: (CH3)2CHNCOCH2CH2OC(O)CH3 + HCl → (CH3)2CHNCOCH2CH2OC(O)CH3·HCl
2. S-methylation method:
a. Step 1: First, 3-aminopropionitrile is reduced to 3-aminopropanol by hydrogenation (same as the Rosenmund-Von Braun reaction).
b. Step 2: react 3-aminopropanol with methyl sodium iodide, and carry out S-methylation reaction under alkaline conditions.
Reaction formula: CH3I + NH2CH2CH2OH → NH2CH2CH2OCH3 + HI
c. Step 3: S-methyl-Pregabalin is converted to the hydrochloride form by hydrochloric acid treatment.
Reaction formula: NH2CH2CH2OCH3·HCl
3. Phthalic acid amide method:
a. Step 1: First, the anhydride is formed by reacting phthalic dicarboxylic anhydride with 2-aminoethanol.
Reaction formula: C6H4(CO)2Cl2 + H2NCH2CH2OH → C6H4(CO)2(ONHCH2CH2OH)
b. Step 2: React anhydride with γ-butyrolactone under acidic conditions to form an intermediate ring.
Reaction formula: C6H4(CO)2(ONHCH2CH2OH) + C4H6O2 → C9H7NO3
c. Step 3: Convert the ring to Pregabalin by reduction and alkylation.
d. Step 4: Finally, pregabalin is converted to hydrochloride form by hydrochloric acid treatment.
Please note that the above steps may also include the use of other intermediates and auxiliary reagents, and the specific reaction conditions and operation details can be optimized and adjusted according to the specific synthesis scheme. In addition, when performing any chemical synthesis, it is important to follow the relevant safety procedures and perform it in a suitable laboratory environment.
1. Chemical structure analysis:
The naming process of pregabalin started with the analysis of its chemical structure. Chemists determine the functional groups of a molecule by analyzing its makeup and how it is connected. For Pregabalin, its chemical name "(3S)-3-{[(2S)-1-(methyl)ethyl]amino}propanoic acid" reveals the main functional groups in the molecule and their layout.
1.1. Functional group:
The chemical structure of Pregabalin contains several key functional groups that play an important role in pharmacological activity and efficacy. First, we can see a carboxylic acid group (-COOH) at the end of the molecule, a common feature of many organic acids. Second, there is an amino group (-NH2) attached to the carbon atom, which is a common amino group in many organic compounds.
1.2. Carbon skeleton:
The carbon skeleton of Pregabalin consists of 3 carbon atoms with an asymmetric carbon atom in the center. The other two carbon atoms are attached to the carboxylic acid group and the amino group respectively. The presence of this carbon skeleton allows the molecule to have stereoisomers.
1.3. Stereoisomers:
Pregabalin is a chiral compound with stereoisomers. In its structure, a central carbon atom (Cα) is linked to a methyl group (CH3), an amino group (NH2) and a carboxyl group (COOH). In Pregabalin, the four linkages around the carbon atom are: two H (hydrogen atoms) and one methyl group (CH3) on the same plane, while the other is an amino group (NH2). This structural feature makes Pregabalin have two enantiomers, namely (S)-Pregabalin and (R)-Pregabalin.
1.4. Spatial configuration:
According to the presence of stereoisomers, Pregabalin exhibits an asymmetric spatial configuration. Its stereoisomers can be described by the orientation around Cα. In (S)-Pregabalin, the methyl and amino groups are on the same side, while in (R)-Pregabalin, they are on opposite sides. These differences in spatial configuration may have an impact on the activity and physicochemical properties of the drug.
1.5. Molecular weight:
The relative molecular mass of Pregabalin is 159.23 g/mol. Molecular weight provides information on the overall size and mass of the molecule. It is obtained by adding the relative atomic masses of each atom.
It should be noted that the molecular structure of Pregabalin can be analyzed and verified by further experimental and technical means, such as nuclear magnetic resonance (NMR) spectroscopy and crystallographic methods. These experiments could provide more detailed information about bond lengths, bond angles, and stereo configurations, thereby deepening the understanding of Pregabalin's molecular structure.
2. Drug classification:
When naming a drug, it is important to understand its pharmacological class. Pregabalin belongs to the gamma-aminobutyric acid (GABA) analogs with antiepileptic and analgesic effects. This information helps to position Pregabalin in drug nomenclature.
3. International Nonproprietary Name (INN):
INN is determined by the World Health Organization (WHO) and the International Nonproprietary Names (INN) Committee. The committee's goal is to provide a recognized, non-proprietary nomenclature system for medicines worldwide that is easy for healthcare professionals and patients to use. Pregabalin is accepted as its generic name and the corresponding INN is registered, pregabalin.
4. Trademark Law:
Trademark law is the legal framework used to protect and promote trade names. When naming a drug, pharmaceutical companies often choose a special brand name as their trade name to differentiate their product in the market. For example, in the United States, Gabapentin is marketed by Pfizer under the brand name "Lyrica".
5. FDA approval:
Pregabalin was originally developed by Pfizer and was approved by the US Food and Drug Administration (FDA) in 2004. Before being approved by the FDA, Pregabalin went through a rigorous clinical trial and evaluation process to ensure its safety and efficacy.