Drug Synthesis and Organic Chemistry Review

Vocabulary practice flashcards covering synthetic routes, reagents, and intermediate chemical structures for major active pharmaceutical ingredients from organic chemistry notes.

Vitamin K1 Synthesis

A condensation reaction between 2-methyl-1,4-naphthoquinone ($\text{2-metylo-1,4-naftochinon}$) and phityl bromide ($\text{bromek fitylu}$).

Vitamin K3 Synthesis

Oxidation ($\text{utlenianie}$) of 2-methylnaphthalene ($\text{2-metylonaftalen}$) using chromic trioxide in sulfuric acid ($\text{CrO}_3 / \text{H}_2\text{SO}_4$) to yield 2-methyl-1,4-naphthoquinone.

Vitamin PP (B3) Synthesis

Oxidation of 3-methylpyridine ($\text{3-metylopirydyna}$) with $\text{KMnO}_4$ to nicotinic acid ($\text{kwas nikotynowy}$), esterification with $\text{C}_2\text{H}_5\text{OH}/\text{H}_2\text{SO}_4$ to ethyl nicotinate ($\text{nikotynian etylu}$), and ammonolysis with $\text{NH}_3$ to nicotinamide ($\text{nikotynamid}$).

Vitamin C Synthesis

Reduction of D-glucose to D-sorbitol ($\text{H}_2/\text{Ni}$), suboxidation with Acetobacter to L-sorbose, protection with acetone/$\text{H}_2\text{SO}_4$, oxidation with alkaline $\text{KMnO}_4$, acidic hydrolysis ($\text{HCl (aq)}$), thermal dehydration ($-\text{H}_2\text{O}$), and enolization to ascorbic acid.

Clemastine Synthesis

Friedel-Crafts C-acylation to 4-chlorobenzophenone, Grignard reaction yielding tertiary alcohol 1-(4-chlorophenyl)-1-phenylethanol, and condensation (alkylation) with 2-(2-chloroethyl)-1-methylpyrrolidine using $\text{NaOH}$ to yield clemastine.

Cetirizine Synthesis

Friedel-Crafts acylation to 4-chlorobenzophenone, reduction with $\text{NaBH}_4/\text{CH}_3\text{OH}$, conversion with aqueous $\text{HCl/toluene}$ to chloro derivative, coupling with piperazine, alkylation with methyl 2-(2-chloroethoxy)acetate using $\text{Na}_2\text{CO}_3$, and basic hydrolysis with $\text{KOH}$.

Loratadine Synthesis

Reaction of carbonitrile derivative with 1-methylpiperidin-4-ylmagnesium bromide in THF followed by $2\text{N }\text{HCl}$, intramolecular cyclization with $\text{HF}/\text{BF}_3$, and carbamoylation with ethyl chloroformate ($\text{ClCOOC}_2\text{H}_5$) and triethylamine ($\text{TEA}$) at $80\text{ }^\text{o}\text{C}$.

Phenobarbital Synthesis

Conversion of phenylacetonitrile to ethyl phenylacetate, condensation with diethyl oxalate to ethyl diethyl phenyloxaloacetate, decarbonylation at $170\text{ }^\text{o}\text{C}$ to diethyl phenylmalonate, ethylation with $\text{C}_2\text{H}_5\text{Br}/\text{C}_2\text{H}_5\text{ONa}$, and condensation with urea ($\text{H}_2\text{NCONH}_2$) to 5-ethyl-5-phenylbarbituric acid.

Valproic Acid Synthesis

Reaction of $\text{NaCN}$ with sodium chloroacetate to sodium cyanoacetate, hydrolysis with $\text{NaOH}$ to sodium malonate, acidification with $\text{H}_2\text{SO}_4$, esterification to diethyl malonate, dipropylation with $2\text{ }\text{C}_3\text{H}_7\text{Br}/\text{C}_2\text{H}_5\text{ONa}$, hydrolysis to dipropylmalonic acid, and thermal decarboxylation at $170\text{ }^\text{o}\text{C}$ ($-\text{CO}_2$) to 2-propylvaleric acid.

Diazepam Synthesis

Friedel-Crafts acylation yielding 2-amino-5-chlorobenzophenone, cyclization with glycine ethyl ester in pyridine to 7-chloro-5-phenyl-3H-1,4-benzodiazepin-2-one, and amide nitrogen alkylation using dimethyl sulfate ($(\text{CH}_3)_2\text{SO}_4$) and sodium methoxide ($\text{CH}_3\text{ONa}$).

Alprazolam Synthesis

Condensation of 2-amino-5-chlorobenzophenone with glycine ethyl ester, thionation with phosphorus pentasulfide ($\text{P}_2\text{S}_5$), condensation with acetylohydrazine ($\text{CH}_3\text{CONHNH}_2$), and thermal cyclization at $250\text{ }^\text{o}\text{C}$ to form 8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine.

Estazolam Synthesis

Reaction of benzodiazepine thione precursor with hydrazine ($\text{NH}_2\text{NH}_2$) followed by condensation with triethyl orthoformate ($(\text{CH}_3\text{O})_3\text{CH}$) to form 8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine.

Guaiacol Synthesis

Diazotization of o-anisidine with $\text{NaNO}_2/\text{H}_2\text{SO}_4$ to form 2-methoxybenzenediazonium sulfate, followed by aqueous copper sulfate ($\text{H}_2\text{O}/\text{CuSO}_4$) hydrolysis to yield 2-methoxyphenol.

p-Aminosalicylic Acid (PAS) Synthesis

Carboxylation of 3-aminophenol with potassium bicarbonate ($\text{KHCO}_3$) and carbon dioxide ($\text{CO}_2$) at $85\text{ }^\text{o}\text{C}$ and $35\text{ }\text{atm}$.

Parabens Synthesis (Modified Kolbe-Schmitt)

Reaction of phenol with $\text{KOH}$ to form potassium phenolate, carboxylation with $\text{CO}_2$ ($100\text{ }^\text{o}\text{C} \rightarrow 150\text{ }^\text{o}\text{C}$), acidification with aqueous $\text{HCl}$ to 4-hydroxybenzoic acid, and esterification with various alcohols using $\text{H}_2\text{SO}_4$.

Chlorquinaldol Synthesis

Skraup condensation of 2-aminophenol with crotonaldehyde derivative in $\text{HCl}/\text{CH}_3\text{OH}$ to 2-methyl-8-hydroxyquinoline, followed by chlorination with $\text{Cl}_2$ to yield 5,7-dichloro-2-methyl-8-hydroxyquinoline.

Rivanol Synthesis

Condensation of 2-chloro-4-nitrobenzoic acid with p-phenetidine ($\text{Cu}, \text{K}_2\text{CO}_3, 115\text{ }^\text{o}\text{C}$), cyclization with $\text{POCl}_3/\text{xylene}$ to 2-ethoxy-6-nitro-9-chloroacridine, amination with $\text{NH}_3$, and catalytic reduction ($\text{H}_2/\text{Raney-Ni}$) to 6,9-diamino-2-ethoxyacridine.

Chlorpromazine Synthesis

Condensation of 2-chlorobenzoic acid with 3-chloroaniline ($\text{Cu, K}_2\text{CO}_3, 110\text{ }^\text{o}\text{C}, \text{butanol}$), iron-catalyzed decarboxylation ($\text{Fe, }-\text{CO}_2$) to 3-chloro-N-phenylaniline, sulfur fusion ($\text{S}$) to 2-chlorophenothiazine, and alkylation with $\text{NaNH}_2$ and 3-chloro-N,N-dimethylpropan-1-amine.

Haloperidol Synthesis

Friedel-Crafts acylation of fluorobenzene with 4-chlorobutyryl chloride ($\text{AlCl}_3$) yielding 4-chloro-4'-fluorobutyrophenone, followed by nucleophilic alkylation with 4-(4-chlorophenyl)-4-hydroxypiperidine.

Venlafaxine Synthesis

Condensation of (4-methoxyphenyl)acetonitrile with cyclohexanone in basic medium, catalytic hydrogenation ($\text{H}_2/\text{kat}$) of nitrile group to primary amine, and reductive N-dimethylation with formaldehyde and formic acid ($\text{HCHO, HCOOH}$).

Diclofenac Synthesis

Coupling of bromobenzene with N-acetyl-2,6-dichloroaniline to 2,6-dichlorodiphenylamine, acylation with chloroacetyl chloride ($\text{CICH}_2\text{COCl}$), intramolecular Friedel-Crafts cyclization ($\text{AlCl}_3$) to 1-(2,6-dichlorophenyl)indolin-2-one, and basic/acidic ring-opening hydrolysis ($\text{1. OH}^-, \text{2. HCl}$).

Ibuprofen Synthesis

Alkylation of benzene to isobutylbenzene, Friedel-Crafts acylation with acetyl chloride ($\text{AlCl}_3$) to p-isobutylacetophenone, Darzens reaction with ethyl chloroacetate to an $\alpha,\beta$-epoxy ester, hydrolysis/decarboxylation to aldehyde intermediate, and oxidation to 2-[4-(2-methylpropyl)phenyl]propanoic acid.

Celecoxib Synthesis

Diazotization of sulfanilamide ($\text{HCl, NaNO}_2, \text{H}_2\text{O}, -5\text{ }^\text{o}\text{C}$) followed by reduction with $\text{SnCl}_2$ to 4-hydrazinobenzenesulfonamide, and condensation with 4,4,4-trifluoro-1-(4-methylphenyl)butane-1,3-dione in ethanol at $75\text{ }^\text{o}\text{C}$.

Sulfacetamid Synthesis

Chlorosulfonation of acetanilide with $\text{ClSO}_3\text{H}$ to ASC, amidation to 4-acetamidobenzenesulfonamide, acetylation of the sulfonamide group with acetic anhydride ($(\text{CH}_3\text{CO})_2\text{O}$), and selective alkaline hydrolysis with $\text{NaOH}$ at $30\text{ }^\text{o}\text{C}$.

Clotrimazole Synthesis

Photochemical chlorination of 2-chlorotoluene ($\text{Cl}_2/h\nu$) to 2-chlorobenzotrichloride, Friedel-Crafts alkylation of benzene with $\text{AlCl}_3$ to form 2-chlorotriphenylmethyl chloride, and N-alkylation of imidazole in the presence of triethylamine ($\text{TEA}$).

Pyrantel Synthesis

Condensation of N-methyl-N-acetyl-$\beta$-aminopropionitrile derivative to 1,2-dimethyltetrahydropyrimidine, followed by condensation with thiophene-2-carbaldehyde ($\text{tiofeno-2-karbaldehyd}$) to yield 1,4,5,6-tetrahydro-1-methyl-2-[2-(2-thienyl)ethenyl]pyrimidine.

Furosemide Synthesis

Reaction of 2,4-dichlorobenzoic acid with chlorosulfonic acid ($\text{ClSO}_3\text{H}$) to 2,4-dichloro-5-sulfonylchloride benzoic acid, amidation with $\text{NH}_3$ to 2,4-dichloro-5-sulfamoylbenzoic acid, and nucleophilic displacement with furfurylamine ($\text{furfuryloamina}$).

Omeprazole Synthesis

Condensation of 1,2-diamino-4-methoxybenzene with potassium ethyl xanthate to 5-methoxy-1H-benzimidazole-2-thiol; conversion of 2-(hydroxymethyl)-4-methoxy-3,5-dimethylpyridine with $\text{SOCl}_2$ to chloro derivative; coupling in $40\%\text{ NaOH}$ and oxidation with peroxyacids.

Bisacodyl Synthesis

Catalytic oxidation of 2-methylpyridine with $\text{V}_2\text{O}_5$ to picolinaldehyde ($\text{aldehyd pikolinowy}$), condensation with phenol (2 eq) in sulfuric acid to 4,4'-(2-pyridylmethylene)diphenol, and acetylation with acetic anhydride ($(\text{CH}_3\text{CO})_2\text{O}$) and sodium acetate.

Sulfasalazine Synthesis

Step 1: Chichibabin amination of pyridine to 2-aminopyridine, sulfonation with 4-nitrobenzenesulfonyl chloride, and reduction ($+3\text{ }\text{H}_2, -2\text{ }\text{H}_2\text{O}$) to sulfapyridine. Step 2: Diazotization with $\text{NaNO}_2/\text{HCl}$ and diazo coupling with salicylic acid in $\text{KOH}$.

Procaine Synthesis

Esterification of 4-nitrobenzoic acid with ethanol/$\text{H}_2\text{SO}_4$ to ethyl 4-nitrobenzoate (benzocaine intermediate), transesterification with diethylaminoethanol, and iron-catalyzed nitro group reduction ($\text{Fe, CH}_3\text{COOH}$).

Lidocaine Synthesis

Reaction of 2,6-dimethylaniline with chloroacetyl chloride to form 2-chloro-N-(2,6-dimethylphenyl)acetamide, followed by nucleophilic substitution with diethylamine ($\text{NH}(\text{C}_2\text{H}_5)_2$).

Carbachol Synthesis

Reaction of choline chloride with phosgene ($\text{COCl}_2$) to form a 2-chloroethyl chloroformate intermediate or chlorocarbonyl choline chloride, followed by amination with ammonia ($\text{NH}_3$).

Neostigmine Synthesis

Reaction of 3-dimethylaminophenol with dimethylcarbamoyl chloride ($\text{Cl-CO-N(CH}_3)_2$) to form 3-(N,N-dimethylcarbamoyloxy)-N,N-dimethylaniline, followed by quaternization with dimethyl sulfate ($(\text{CH}_3)_2\text{SO}_4$).

Drotaverine Synthesis

Bischler-Napieralski cyclization of 2-(3,4-diethoxyphenyl)-N-[2-(3,4-diethoxyphenyl)ethyl]acetamide using phosphorus oxychloride ($\text{POCl}_3$) to yield 6,7-diethoxy-1-(3,4-diethoxybenzylidene)-1,2,3,4-tetrahydroisoquinoline.

Baclofen Synthesis

Synthesis starting from 3-(p-chlorophenyl)glutaric acid imide undergoing Hofmann rearrangement with $\text{Br}_2/\text{NaOH}$ or catalytic reduction ($\text{H}_2/\text{PtO}_2$) of cyano derivative to yield 3-(p-chlorophenyl)-4-aminobutyric acid.

Captopril Synthesis

Reaction of methacrylic acid or (2S)-3-acetylthio-2-methylpropanoic acid chloride with L-proline in $\text{NaOH}$ to yield (2S)-1-(3-acetylthio-2-methylpropanoyl)-L-proline, followed by deacetylation with $\text{NH}_3$ to yield (2S)-1-(3-mercapto-2-methylpropanoyl)-L-proline.

Perindopril Synthesis

Diazotization of aniline, condensation, Fischer indolization, and hydrogenation to octahydro-1H-indole-2-carboxylic acid; benzyl ester protection, DCC/HOBt coupling with N-[(S)-1-carboxybutyl]-(S)-alanine, and catalytic hydrogenolysis ($\text{Pd/C}$).

Losartan Synthesis

Reaction of ethyl valerimidate with dihydroxyacetone to 2-butyl-5-hydroxymethyl-1H-imidazole, chlorination with NCS to 2-butyl-4-chloro-5-hydroxymethyl-1H-imidazole, alkylation with 4'-(bromomethyl)-[1,1'-biphenyl]-2-carbonitrile, and tetrazole formation with $\text{NaN}_3/\text{NH}_4\text{Cl}$ in DMF at $120\text{ }^\text{o}\text{C}$.

Bisoprolol Synthesis

Reaction of 4-hydroxybenzyl alcohol with 2-isopropoxyethanol ($\text{H}_2\text{SO}_4, 150\text{ }^\text{o}\text{C}$) to 4-(2-isopropoxyethoxymethyl)phenol, alkylation with epichlorohydrin, and epoxide ring-opening with isopropylamine.

Amiodarone Synthesis

Acylation of benzofuran with butyric anhydride ($\text{H}_3\text{PO}_4$) to 2-butylbenzofuran, acylation with 4-methoxybenzoyl chloride ($\text{SnCl}_4$), demethylation ($\text{KI/HOAc}$), iodination ($\text{I}_2$), and alkylation with 2-chloro-N,N-diethylethan-1-amine.

Verapamil Synthesis

Alkylation of (3,4-dimethoxyphenyl)acetonitrile with 2-chloropropane using $\text{NaNH}_2$, followed by coupling with 3-chloro-N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylpropan-1-amine in the presence of $\text{NaNH}_2$.

Amlodipine Synthesis

Hantzsch dihydropyridine synthesis using ethyl 4-chloroacetoacetate, 2-azidoethanol, 2-chlorobenzaldehyde, and methyl 3-aminocrotonate, followed by reduction of the azido group ($\text{Zn/HCl}$ or $\text{H}_2/\text{Pd-C}$) to 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate.

Fenofibrate Synthesis

Friedel-Crafts acylation of methoxybenzene with 4-chlorobenzoyl chloride ($\text{AlCl}_3$), HBr demethylation to 4-chloro-4'-hydroxybenzophenone, Williamson ether synthesis, and esterification with isopropyl alcohol ($\text{H}_2\text{SO}_4$) under reflux for 12 hours.

Acenocoumarol Synthesis

Acylation/cyclization of methyl salicylate to 4-hydroxycoumarin, aldol condensation of 4-nitrobenzaldehyde with acetone to 4-(4-nitrophenyl)but-3-en-2-one, and Michael addition of 4-hydroxycoumarin to the enone.

Ticlopidine Synthesis

Quaternization of thieno[3,2-c]pyridine with 1-chloro-2-(chloromethyl)benzene, followed by sodium borohydride ($\text{NaBH}_4$) reduction of the pyridinium ring.

Tramadol Synthesis

Mannich reaction of cyclohexanone with formaldehyde ($\text{HCHO}$) and dimethylamine ($\text{HN(CH}_3)_2$) to form 2-[(dimethylamino)methyl]cyclohexan-1-one, followed by Grignard addition with 3-methoxyphenylmagnesium bromide.

Fentanyl Synthesis

Reductive amination of 4-piperidone with phenethylaldehyde ($\text{NaBH(OAc)}_3$), reductive amination with aniline to N-phenyl-1-(2-phenylethyl)piperidin-4-amine, and acylation with propionic anhydride.

Caffeine Synthesis (Traube Synthesis)

Condensation of urea with ethyl cyanoacetate to 6-aminouracil, nitrosation ($\text{NaNO}_2/\text{HCl}$), reduction ($\text{Zn/H}_2\text{SO}_4$) to 5,6-diaminouracil, formylation with $\text{HCOOH}$, cyclization to xanthine, and N-methylation with dimethyl sulfate or methyl chloride.

Naphazoline Synthesis

Condensation of 1-naphthylacetic acid or derivative with ethylenediamine followed by treatment with $\text{HCl}$ to form 2-(naphthalen-1-ylmethyl)-4,5-dihydro-1H-imidazole hydrochloride.

Salbutamol Synthesis

Friedel-Crafts acylation of methyl salicylate with chloroacetyl chloride ($\text{AlCl}_3$), substitution with N-benzyl-tert-butylamine, and catalytic reduction ($\text{Pd/C}$) to reduce the ketone and remove the benzyl protecting group.

Noradrenaline Synthesis

Reaction of 1,2-dihydroxybenzene (catechol) with chloroacetyl chloride in $\text{POCl}_3$, amination with ammonia ($\text{NH}_3$), and catalytic hydrogenation with Raney nickel ($\text{H}_2/\text{Raney-Ni}$).

Hydroxyzine Synthesis

Reduction of 4-chlorobenzophenone with $\text{NaBH}_4$ to (4-chlorophenyl)phenylmethanol, chlorination to 1-chloro-1-(4-chlorophenyl)-1-phenylmethane, and alkylation with 2-[2-(piperazin-1-yl)ethoxy]ethanol.

Progesterone Synthesis

Degradation of diosgenin to 16-dehydropregnenolone acetate, hydrogenation ($\text{H}_2/\text{Pd}$) to pregnenolone, and Oppenauer oxidation using aluminum isopropoxide ($\text{Al[OCH(CH}_3)_2]_3$).

Budesonide Synthesis

Acid-catalyzed acetalization of 16$\alpha$-hydroxyprednisolone with butyraldehyde (butanal) in ethanol ($\text{C}_2\text{H}_5\text{OH}$).

Thiouracil Synthesis

Condensation of thiourea ($\text{H}_2\text{NCSNH}_2$) with ethyl acetoacetate or ethyl oxohexanoate in the presence of sodium ethoxide ($\text{C}_2\text{H}_5\text{ONa}$) to yield 6-methyl-2-thiouracil or 6-propyl-2-thiouracil.

Thiamazole Synthesis

Reaction of N-(dipropoxymethyl)ethanamine with potassium thiocyanate ($\text{KSCN}$) and $\text{HCl}$ to form 1,3-dihydro-1-methyl-2H-imidazole-2-thione.

Acyclovir Synthesis

Benzoylation of ethylene glycol to 2-hydroxyethyl benzoate, chloromethylation with $\text{HCHO/HCl(g)}$, alkylation of guanine in $\text{K}_2\text{CO}_3/\text{DMF}$, and amidation/deprotection with methanolic ammonia ($\text{NH}_3/\text{CH}_3\text{OH}$).

Azidothymidine (AZT) Synthesis

Reaction of thymidine with DIAD/$\text{PPh}_3$ to form a 2,3'-anhydrothymidine intermediate, followed by nucleophilic ring opening with sodium azide ($\text{NaN}_3$) in DMF at $125\text{ }^\text{o}\text{C}$.

Denotivir Synthesis

Benzoylation of 3-methyl-5-aminoisothiazole-4-carboxylic acid, chlorination with $\text{SOCl}_2$ to the acid chloride, and amidation with 4-chloroaniline.

Busulfan Synthesis

Reaction of butane-1,4-diol ($\text{HO-(CH}_2)_4\text{-OH}$) with methanesulfonyl chloride ($\text{CH}_3\text{-SO}_2\text{Cl}$) in ethanol to yield butane-1,4-diyl dimethanesulfonate.

6-Mercaptopurine Synthesis

Cyclization of 4,5-diaminopyrimidine derivative with formamide ($\text{HCONH}_2$) to hypoxanthine, followed by thionation with phosphorus pentasulfide ($\text{P}_2\text{S}_5$).

5-Fluorouracil Synthesis

Condensation of S-alkylisothiourea with ethyl 2-fluoro-3-hydroxyacrylate to form 2-alkylthio-4-hydroxy-5-fluoropyrimidine, followed by acid hydrolysis ($\text{H}_2\text{O}/\text{H}^+$).

Methotrexate Synthesis

Condensation of 2,4-diamino-6-(bromomethyl)pteridine with N-[4-(methylamino)benzoyl]glutamic acid.