Routes to Essential Medicines. Peter J. Harrington

Чтение книги онлайн.

СКАЧАТЬ with 4‐methoxybenzoyl chloride (Friedel–Crafts Acylation). The phenol is formed by demethylation of the ether. The phenol is iodinated in both ortho positions.

      The retrosynthetic analysis ends with specialty chemical(s), petrochemical(s), or biochemical(s) starting materials. Specialty chemical and petrochemical starting materials are highlighted with a box to direct the reader to an Appendix. Appendix A contains the specialty chemicals used in this workbook. One retrosynthetic analysis is provided for each specialty chemical. It is important to emphasize that specialty chemicals are often manufactured by more than one route. The preferred route often changes with the implementation of new manufacturing technologies and with changes in availability and cost of petrochemical and biochemical raw materials. Each specialty chemical retrosynthetic analysis ends with petrochemical(s) or biochemical(s) available in bulk from many suppliers. Appendix B lists the petrochemicals extracted or produced from coal, crude oil, or natural gas that are used in this workbook. Appendix C lists the biochemicals that are used in this workbook.

In the optional Extended Discussion, students are tasked to propose and evaluate alternative routes, reactions, or reagents encountered in their online search work.

      A course based on this workbook could be organized in many ways: medicines for pain, medicines containing fluorine, medicines made using a Diels–Alder Reaction, etc. Course development will be facilitated by the provided Indices (name reactions, starting materials from the chiral pool, diazonium salt reactions, epoxide ring‐opening reactions, fluorine‐containing target molecules, furans, imidazoles, nucleophilic aromatic substitution reactions, oxidations, peptides, photochemistry, purines, pyrazines, pyridines, pyrimidines, quinolines, symmetrical molecules, thiazoles, thioethers, triazoles.)

      Appendices A, B, and C and a complete list of the References used in preparation of the workbook are available on the companion website.

       www.wiley.com/go/Harrington/routes_essential_medicine

A

      Abacavir

      Antiviral Medicines/Antiretrovirals/Nucleoside or Nucleotide Reverse Transcriptase Inhibitors

       When two chiral carbons are separated by one or more atoms, disconnections often lead back to an intermediate with the two chiral carbons next to each other and formed in the same reaction.

      Discussion. Cyclopropanamine is introduced by chloride displacement in the final step (the chloropurine partner is also used to make the AIDS drug carbovir.) The imidazole ring of the purine is formed from the formamide (Traube Purine Synthesis). A C─N bond is formed by displacement of chloride from the symmetrical dichloropyrimidine by the amine of (1S,4R)‐4‐amino‐2‐cyclopentene‐1‐methanol.

The 2,5‐diaminopyrimidine 5‐formamide is formed from the 2,5‐diaminopyrimidine and formic acid. 2,5‐Diamino‐4,6‐dichloropyrimidine is formed from 2,5‐diamino‐4,6‐dihydroxypyrimidine. 2,5‐Diamino‐4,6‐dihydroxypyrimidine is formed by hydrolysis of the 5‐acetamide. 5‐Acetamido‐2‐amino‐4,6‐dihydroxypyrimidine ring is formed from guanidine and diethyl acetamidomalonate (Pinner Pyrimidine Synthesis).

      (1S,4R)‐4‐Amino‐2‐cyclopentene‐1‐methanol and the (1R,4S)‐enantiomer are separated by resolution. The amino alcohols are formed by reduction of the amides (Vince Lactam). The amides are formed by displacement of methanesulfinate by hydroxide.

      The 2‐azabicyclo[2.2.1]hepta‐2,5‐dienes are formed by [4 + 2]‐cycloaddition of cyclopentadiene with methanesulfonyl cyanide (Diels–Alder Cycloaddition). Methanesulfonyl cyanide is formed from sodium methanesulfinate and cyanogen chloride. Sodium methanesulfinate is formed by reduction of methanesulfonyl chloride.

      Extended Discussion

      Draw the structures of the retrosynthetic analysis of one alternative route to abacavir using a disconnection of the C─N bond joining the purine ring to the cyclopentene ring. Include the structures of the retrosynthetic analysis of any organic starting material(s) from petrochemical or biochemical raw materials.

Acetazolamide

      Ophthalmological Preparations/Miotics and Antiglaucoma Medicines

       A sulfonyl chloride attached to an aromatic ring may be formed by oxidation of the thiol.

      Discussion. Acetazolamide is formed in just three steps from 5‐amino‐1,3,4‐thiadiazole‐2‐thiol. The sulfonamide is formed from the sulfonyl chloride in the final step. The sulfonyl chloride is formed by oxidation of the thiol. The amide is formed by acetylation of the amine using acetic anhydride.

      Extended Discussion

      Draw the structures of the retrosynthetic analysis of one alternative route to the starting material 5‐amino‐1,3,4‐thiadiazole‐2‐thiol. List the pros for the route presented and the alternative route and select one route as the preferred route.

Acetylcysteine

      Antidotes/Specific

       A chiral carbon in a single‐enantiomer molecule is often delivered in a starting material.

      Discussion. N‐Acetyl‐L‐cysteine is formed by acetylation of L‐cysteine with acetic anhydride. L‐Cysteine is produced by fermentation.

Acetylsalicylic Acid

      Medicines for Pain and Palliative Care/Non‐Opioids and Non‐Steroidal Anti‐Inflammatory Medicines

      Antimigraine СКАЧАТЬ