Pharmaceutical Synthesis Methods and Salt Formation
Diphenhydramine HCl Synthesis
Common synthesis route
- Starting materials: benzhydrol and 2-(dimethylamino)ethanol.
- Reaction: benzhydrol is reacted with 2-(dimethylamino)ethanol in the presence of an acid catalyst (such as HCl or sulfuric acid) to form diphenhydramine base.
- Formation of HCl salt: the diphenhydramine base is converted to its HCl salt for stability and solubility.
Process
- Step 1: React benzhydrol with 2-(dimethylamino)ethanol under acidic conditions.
- Step 2: Form the HCl salt by treating the base with HCl gas or aqueous HCl.
Diphenhydramine HCl is an antihistamine used for allergies, insomnia, and other conditions.
Promethazine HCl Synthesis
Common synthesis route
- Starting materials: phenothiazine and 2-chloro-N,N-dimethylethanamine (or similar intermediates).
- Reaction: phenothiazine is reacted with 2-chloro-N,N-dimethylethanamine in the presence of a base (for example, sodium amide) to form promethazine base.
- Formation of HCl salt: the promethazine base is converted to its HCl salt for stability and solubility.
Process
- Step 1: React phenothiazine with 2-chloro-N,N-dimethylethanamine.
- Step 2: Form the HCl salt by treating the base with HCl gas or aqueous HCl.
Promethazine HCl is used for allergies, nausea, and sedation.
Triprolidine HCl Synthesis
Common synthesis route
- Starting materials: 2-pyridylacetonitrile and p-tolylaldehyde are reacted to form an intermediate.
- Reaction: the intermediate undergoes cyclization and reduction steps to form triprolidine base.
- Formation of HCl salt: the triprolidine base is converted to its HCl salt for stability and solubility.
Process
- Step 1: React 2-pyridylacetonitrile with p-tolylaldehyde.
- Step 2: Cyclize and reduce the intermediate.
- Step 3: Form the HCl salt by treating the base with HCl gas or aqueous HCl.
Triprolidine HCl is an antihistamine used for allergies.
Cimetidine Synthesis
Common synthesis route
- Starting materials: cyanoguanidine and 2-chloroacetamide reacted with N-methyl-1-(methylthio)ethan-1-imine (or similar intermediates).
- Reaction: the intermediate undergoes cyclization and substitution reactions to form cimetidine.
Process
- Step 1: React cyanoguanidine with N-methyl-1-(methylthio)ethan-1-imine.
- Step 2: Introduce the imidazole ring and substitute with the appropriate side chain.
Cimetidine is an H2 receptor antagonist used to reduce stomach acid.
Mechlorethamine Synthesis
Common synthesis route
- Starting materials: N-methyl-2,2′-dichlorodiethylamine or related precursors.
- Reaction: react methylamine with ethylene oxide to form an intermediate, followed by chlorination to form mechlorethamine.
Process
- Step 1: React methylamine with ethylene oxide to form N-methyl-diethanolamine.
- Step 2: Chlorinate with thionyl chloride or a similar reagent to form mechlorethamine.
Mechlorethamine is a nitrogen mustard used in chemotherapy (for example, Hodgkin’s lymphoma).
Mercaptopurine Synthesis
Common synthesis route
- Starting materials: hypoxanthine or related purine derivatives.
- Reaction: hypoxanthine is reacted with phosphorus pentasulfide (P4S10) to introduce the thiol group, forming mercaptopurine.
Process
- Step 1: React hypoxanthine with P4S10 to form 6-mercaptopurine.
Mercaptopurine is an antimetabolite used in chemotherapy for leukemia.
Methotrexate Synthesis
Common synthesis route
- Starting materials: pteridine derivatives and p-aminobenzoic acid (or related intermediates).
- Reaction: the synthesis involves coupling p-aminobenzoic acid with a pteridine ring, followed by introduction of the glutamic acid moiety.
Process
- Step 1: Synthesize the pteridine ring.
- Step 2: Couple with p-aminobenzoic acid.
- Step 3: Add glutamic acid to form methotrexate.
Methotrexate is an antifolate used in chemotherapy and for autoimmune diseases such as rheumatoid arthritis.
Nitroglycerin Synthesis
Common synthesis route
- Starting materials: glycerol and nitric acid (HNO3).
- Reaction: glycerol is nitrated with a mixture of nitric and sulfuric acids to form nitroglycerin.
Process
- Step 1: Mix glycerol with HNO3/H2SO4 under controlled conditions.
- Step 2: Nitration occurs, forming nitroglycerin.
Nitroglycerin is a vasodilator used for angina pectoris.
Nitroglycerin Synthesis
Common synthesis route
- Starting materials: glycerol (propane-1,2,3-triol) and a nitrating mixture of concentrated nitric acid (HNO₃) and sulfuric acid (H₂SO₄).
- Reaction: glycerol undergoes nitration, where the hydroxyl groups are esterified with nitrate groups.
C₃H₅(OH)₃ + 3HNO₃ → C₃H₅(ONO₂)₃ + 3H₂O
Process
- Step 1: Mix glycerol with a chilled nitrating mixture (HNO₃/H₂SO₄) under strict temperature control (<10°C) to prevent explosion.
- Step 2: Separate nitroglycerin from the acid mixture, wash with water, and stabilize.
Isosorbide Dinitrate Synthesis
Common synthesis route
- Starting materials: isosorbide and nitric acid (HNO3).
- Reaction: isosorbide is nitrated with a mixture of nitric and sulfuric acids to form isosorbide dinitrate.
Process
- Step 1: React isosorbide with HNO3/H2SO4 under controlled conditions.
- Step 2: Form isosorbide dinitrate, which is then purified.
Isosorbide dinitrate is a vasodilator used for angina pectoris.
Acetazolamide Synthesis
Common synthesis route
- Starting materials: sulfanilamide and acetyl chloride.
- Reaction: sulfanilamide is reacted with acetyl chloride to introduce the acetyl group, forming acetazolamide.
Process
- Step 1: React sulfanilamide with acetyl chloride.
- Step 2: Form acetazolamide, which is then purified.
Acetazolamide is a carbonic anhydrase inhibitor used for glaucoma, epilepsy, and altitude sickness.
Chlorthiazide Synthesis
Common synthesis route
- Starting materials: 4-amino-6-chloro-1,3-benzenedisulfonamide.
- Reaction: react with formic acid or formamide to form the thiazide ring, producing chlorthiazide.
Process
- Step 1: React 4-amino-6-chloro-1,3-benzenedisulfonamide with formic acid or formamide.
- Step 2: Cyclize to form chlorthiazide.
Chlorthiazide is a thiazide diuretic used for hypertension and edema.
Furosemide Synthesis
Common synthesis route
- Starting materials: 2,4-dichlorobenzoic acid and furfurylamine.
- Reaction: react 2,4-dichlorobenzoic acid with furfurylamine, followed by sulfonation and amidation steps to form furosemide.
Process
- Step 1: React 2,4-dichlorobenzoic acid with furfurylamine.
- Step 2: Introduce sulfonamide and carboxylic acid groups.
Furosemide is a loop diuretic used for edema and hypertension.
Methyldopa Synthesis
Common synthesis route
- Starting materials: L-DOPA (3,4-dihydroxyphenylalanine).
- Reaction: L-DOPA is methylated and decarboxylated to form methyldopa.
Process
- Step 1: Methylate L-DOPA.
- Step 2: Form methyldopa, often as the ethyl ester (methyldopate) for better bioavailability.
Methyldopa is an antihypertensive (central alpha-2 agonist).
Disopyramide Synthesis
Common synthesis route
- Starting materials: 2-phenyl-2-(pyridin-2-yl)acetonitrile or related intermediates.
- Reaction: react with appropriate intermediates to form the disopyramide structure.
Process
- Step 1: Form the core structure via condensation reactions.
- Step 2: Introduce the diisopropylaminoethyl side chain.
Disopyramide is an antiarrhythmic drug (Class Ia).
Warfarin Synthesis
Common synthesis route
- Starting materials: 4-hydroxycoumarin and benzylideneacetone.
- Reaction: Michael addition of 4-hydroxycoumarin to benzylideneacetone, followed by cyclization and reduction to form warfarin.
Process
- Step 1: React 4-hydroxycoumarin with benzylideneacetone.
- Step 2: Form warfarin via cyclization and reduction.
Warfarin is an anticoagulant (vitamin K antagonist).
Warfarin Synthesis
Common synthesis route
- Starting materials: 4-hydroxycoumarin and benzylideneacetone.
- Reaction: Michael addition of 4-hydroxycoumarin to benzylideneacetone, followed by cyclization and reduction to form warfarin.
Process
- Step 1: React 4-hydroxycoumarin with benzylideneacetone.
- Step 2: Form warfarin via cyclization and reduction.
Warfarin is an anticoagulant (vitamin K antagonist).
Tolbutamide Synthesis
Common synthesis route
- Starting materials: p-tolylsulfonamide and butyl isocyanate.
- Reaction: react p-tolylsulfonamide with butyl isocyanate to form tolbutamide.
Process
- Step 1: React p-tolylsulfonamide with butyl isocyanate.
Tolbutamide is a sulfonylurea used for type 2 diabetes.
Benzocaine Synthesis
Common synthesis route
- Starting materials: p-aminobenzoic acid (PABA) and ethanol.
- Reaction: esterify PABA with ethanol in the presence of an acid catalyst (such as sulfuric acid) to form benzocaine.
Process
- Step 1: React PABA with ethanol and H2SO4.
Benzocaine is a local anesthetic used for pain relief.
Procaine Synthesis
Common synthesis route
- Starting materials: p-aminobenzoic acid (PABA) and 2-diethylaminoethanol.
- Reaction: esterify PABA with 2-diethylaminoethanol in the presence of an acid catalyst to form procaine.
Process
- Step 1: React PABA with 2-diethylaminoethanol and an acid catalyst.
Procaine is a local anesthetic.
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Dibucaine Synthesis
Common synthesis route
- Starting materials: 2-butoxyquinoline-4-carboxylic acid and N-(2-diethylaminoethyl)-2-methylpropanamide intermediates.
- Reaction: react intermediates to form dibucaine.
Process
- Step 1: Form the quinoline derivative.
- Step 2: Couple with the amide side chain.
Dibucaine is a local anesthetic.