Proxorphan (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...

), also known as proxorphan tartate (

USAN 280px, "Samguk Sagi" Book 04. Silla's Records. In 512, Usan-guk（于山國）was Ulleungdo（鬱陵島） Usan-guk, or the State of Usan, occupied Ulleung-do and the adjacent islands during the Korean Three Kingdoms period. According to the ...

) (developmental code name BL-5572M), is an

opioid Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioi ...

analgesic An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...

and

antitussive Cold medicines are a group of medications taken individually or in combination as a treatment for the symptoms of the common cold and similar conditions of the upper respiratory tract. The term encompasses a broad array of drugs, includin ...

drug A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhal ...

of the

morphinan Morphinan is the prototype chemical structure of a large chemical class of psychoactive drugs, consisting of opiate analgesics, cough suppressants, and dissociative hallucinogens, among others. Structure Morphinan has a phenanthrene cor ...

family that was never marketed. It acts preferentially as a

κ-opioid receptor The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP, is a G protein-coupled receptor that in humans is encoded by the ''OPRK1'' gene. The KOR is coupled to the G protein Gi/G0 and is one of four related receptors that bind o ...

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonist ...

and to a lesser extent as a

μ-opioid receptor The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical ...

partial agonist.

Synthesis

Starting material for this preparation is ketoester 1, available by one of the classical benzomorphan syntheses. Condensation with the

ylide An ylide or ylid () is a neutral dipolar molecule containing a formally negatively charged atom (usually a carbanion) directly attached to a heteroatom with a formal positive charge (usually nitrogen, phosphorus or sulfur), and in which both ato ...

from

Triethyl phosphonoacetate Triethyl phosphonoacetate is a reagent for organic synthesis Organic synthesis is a special branch of chemical synthesis and is concerned with the intentional construction of organic compounds. Organic molecules are often more complex than in ...

( HWE reaction) affords diester 2.

Catalytic hydrogenation Hydrogenation is a chemical reaction between molecular hydrogen (H2) and another compound or element, usually in the presence of a catalyst such as nickel, palladium or platinum. The process is commonly employed to reduce or saturate organic c ...

proceeds from the less hindered face to afford the corresponding saturated diester (3). The esters are then reduced by means of LiAlH₄ to give the

glycol A diol is a chemical compound containing two hydroxyl groups ( groups). An aliphatic diol is also called a glycol. This pairing of functional groups is pervasive, and many subcategories have been identified. The most common industrial diol is e ...

(4); this undergoes internal ether formation on treatment with acid to form the

pyran In chemistry, pyran, or oxine, is a six-membered heterocyclic, non-aromatic ring, consisting of five carbon atoms and one oxygen atom and containing two double bonds. The molecular formula is C5H6O. There are two isomers of pyran that differ by th ...

ring of 5.

Von Braun reaction The von Braun reaction is an organic reaction in which a tertiary amine reacts with cyanogen bromide to an organocyanamide. An example is the reaction of ''N'',''N''-dimethyl-1-naphthylamine: These days, most chemist have replaced cyanogen b ...

with

BrCN Cyanogen bromide is the inorganic compound with the formula (CN)Br or BrCN. It is a colorless solid that is widely used to modify biopolymers, fragment proteins and peptides (cuts the C-terminus of methionine), and synthesize other compounds. ...

(or

ethyl chloroformate Ethyl chloroformate is the ethyl ester of chloroformic acid. It is a reagent used in organic synthesis for the introduction of the ethyl carbamate protecting group and for the formation of carboxylic anhydrides. Preparation Ethyl chlorofo ...

) followed by

saponification Saponification is a process of converting esters into soaps and alcohols by the action of aqueous alkali (for example, aqueous sodium hydroxide solutions). Soaps are salts of fatty acids, which in turn are carboxylic acids with long carbon chains ...

of the intermediate leads to the 2° amine (6). This is converted to the cyclopropylmethyl derivative 8 by acylation with cyclopropylcarbonyl chloride followed by reduction of the thus formed amide (7) with LiAlH₄. Cleaving off the O-methyl ether with sodium

ethanethiol Ethanethiol, commonly known as ethyl mercaptan, is an organosulfur compound with the formula CH3CH2SH. is a colorless liquid with a distinct odor. Abbreviated EtSH, it consists of an ethyl group (Et), CH3CH2, attached to a thiol group, SH. Its ...

affords proxorphan (9).

References

Analgesics Antitussives Benzomorphans Kappa-opioid receptor agonists Opioids Phenols {{analgesic-stub

Synthesis

See also

References