58-00-4

Basic information

• Product Name: apomorphine
• Synonyms: apomorphine;APOMORPHINE, NASAL, BRITANNIA,4H-DIBENZO[DE-G]QUINOLINE-10,11-DIOL, 5,6,6A,7-TETRAHYDRO-6-METHYL, (R)-;(6AR)-6-METHYL-5,6,6A,7-TETRAHYDRO-4H-DIBENZO[DE,G]QUINOLINE-10,11-DIOL OR APOMORPHINE;(6aS)-5,6,6aα,7-Tetrahydro-6-methyl-4H-dibenzo[de,g]quinoline-10,11-diol;(6aR)-5,6,6a,7-Tetrahydro-6-methyl-4H-dibenzo[de,g]quinoline-10,11-diol;6aβ-Aporphine-10,11-diol;Apomorphin;ApoMorphine-d3
• CAS NO: 58-00-4
• Molecular Formula: C17H17NO2
• Molecular Weight: 267.326
• EINECS: 200-360-0
• Mol File: 58-00-4.mol
• Article Data: 12

Chemical Properties

• Melting Point: 195°C (rough estimate)
• Boiling Point: 410.51°C (rough estimate)
• Flash Point: 268.8 °C
• Appearance: white to grayish powder
• Density: 1.0690 (rough estimate)
• Vapor Pressure: 1.38E-09mmHg at 25°C
• Refractive Index: 1.5400 (estimate)
• PKA: 7.0, 8.92(at 25℃)
• Water Solubility: 20g/L(25 oC)
• CAS DataBase Reference: apomorphine(CAS DataBase Reference)
• NIST Chemistry Reference: apomorphine(58-00-4)
• EPA Substance Registry System: apomorphine(58-00-4)

Safety Data

• Hazardous Substances Data: 58-00-4(Hazardous Substances Data)

Usage

Chemical Properties

Alkaloid; white crystalline mass; turns green on exposure; weakly soluble in water.

Uses

To treat acute poisoning; in the diagnosis and treatment of parkinsonism; a weak sensitizer and a powerful emetic.

Indications

Apomorphine (Uprima) is a short-acting central and peripheral dopamine receptor agonist that can elicit male sexual responses. Dopamine appears to have an important role in normal erectile function. Apomorphine is a D1-like,D2-like dopamine receptor agonist.Apomorphine is not a new drug, and it has been used with limited success in ameliorating the symptoms of Parkinson’s disease and to induce emesis. It is not orally active except for a special buccal formulation, but it can be given parenterally, usually subcutaneously. Apomorphine is rapidly cleared from the kidney because of its high lipid solubility, its large volume of distribution, and its rapid metabolism.

Definition

A derivative of mor- phine that is a dopamine D2 agonist.

Synthesis Reference(s)

Journal of the American Chemical Society, 72, p. 494, 1950 DOI: 10.1021/ja01157a129

Hazard

Poison; central nervous system effects.

Clinical Use

Aside from sildenafil, apomorphine is one of the few orally active (buccal route) pharmacological agents used in the treatment of ED. Apomorphine stimulates penile erection in both normal men and in men who are impotent. Apomorphine can be the drug of choice in patients with coexisting benign prostatic hyperplasia (BPH), coronary artery disease, and hypertension.

Side effects

When formulated into a controlled release sublingual capsule, apomorphine becomes a very effective orally active drug representative of a new class of centrally acting drugs useful in the treatment of ED. It has a narrow range (2 to 6 mg) of effective doses for its erectogenic actions, with the higher doses being more effective in inducing erections.Apomorphine can cause nausea, emesis, drowsiness, and dizziness.

Safety Profile

Poison by ingestion,subcutaneous, intravenous, and intraperitoneal routes.Experimental reproductive effects. Central nervous systemeffects. A powerful emetic. A weak sensitizer and maycause contact dermatitis. When heated to decomposition itemits hig

Purification Methods

Crystallise R-apomorphine from CHCl3 and a little pet ether, also from Et2O with 1 mol of Et2O which it loses at 100o. It sublimes in a high vacuum. It is white but turns green in moist air or in alkaline solution. UV: max 336, 399 (98% EtOH). The di-O-methylether is an oil b 175o/high vacuum, whose picrate crystallises from MeOH and has m 140o (dec). The di-O-acetate crystallises from EtOAc/pet ether with m 127-128o, [] D -88o (c 1, 0.1 N HCl). The di-O-benzoyl derivative has m 156-158o (from EtOH) and []D +43.44o (c 3.3, CHCl3). [Pachorr et al. Chem Ber 35 4377 1902, Beilstein 21 H 246.] NARCOTIC.

InChI:InChI=1/C17H17NO2/c1-18-8-7-10-3-2-4-12-15(10)13(18)9-11-5-6-14(19)17(20)16(11)12/h2-6,13,19-20H,7-9H2,1H3/p+1/t13-/m1/s1

Upstream product

• 124-41-4 sodium methylate 
• 42337-34-8 10,11-bis-benzoyloxy-6-methyl-aporphane 
• 57-27-2 MORPHIN 
• 76-57-3 codeine 
• 58534-36-4 (R)-MDO-Apomorphine 
• 7664-93-9 sulfuric acid 
• 106262-09-3 3,6-bis-benzoyloxy-4,5-epoxy-17-methyl-morphin-7-ene 
• 7647-01-0 hydrogenchloride 
• 86119-84-8 phosphoric acid 
• 467-08-3 6-chloro-4,5-epoxy-3-methoxy-17-methyl-morphin-7-ene 
• 466-95-5 8-chloro-4,5-epoxy-3-methoxy-17-methyl-morphin-6-ene 
• 38291-33-7 (R)-10,11-dimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline 
• 39478-63-2 10,11-dimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline 
• 60048-95-5 8β-chloro-4,5α-epoxy-17-methyl-morphin-6-en-3-ol 

Downstream Products

• 6191-56-6 diacetyl apomorphine 
• 42337-34-8 10,11-bis-benzoyloxy-6-methyl-aporphane 
• 58534-36-4 (R)-MDO-Apomorphine 
• 157643-43-1 (RS)-10-tert-butyldiphenylsilyloxy-11-hydroxyaporphine 
• 210830-69-6 (R)-10-(tert-Butyl-diphenyl-silanyloxy)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinolin-11-ol 
• 83247-89-6 (R)-(-)-11-hydroxyaporphine hydrobromide 
• 210830-71-0 (R)-10-(tert-Butyl-diphenyl-silanyloxy)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline 
• 210830-70-9 Trifluoro-methanesulfonic acid (R)-10-(tert-butyl-diphenyl-silanyloxy)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinolin-11-yl ester 
• 157643-44-2 (RS)-10-tert-butyldiphenylsilyloxy-11-methoxyaporphine 
• 314-19-2 apomorphine hydrochloride 
• 42337-29-1 Di-isobutyryl-apomorphin 
• 38291-33-7 (R)-10,11-dimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline 
• 314-19-2 (±)-apomorphine hydrochloride 

Relevant articles and documents

Synthesis, functional and binding profile of (R)-apomorphine based homobivalent ligands targeting the dopamine D2 receptor

Bivalent ligands represent useful tools to investigate the phenomenon of GPCR dimerization. We synthesized bivalent ligands based on (R)-apomorphine with variations in spacer length, and assessed these compounds in functional and binding assays at the dopamine D2 receptor. The results present novel SAR for bivalent ligands targeting the D2R, and identify a relationship for spacer length with ligand potency, efficacy and affinity. The Royal Society of Chemistry.

Convergent Total Synthesis of (±)-Apomorphine via Benzyne Chemistry: Insights into the Mechanisms Involved in the Key Step

Convergent total synthesis of (±)-apomorphine hydrochloride was accomplished by an approach that employs in the key step a sequence of transformations involving a [4+2]-cycloaddition reaction followed by a hydrogen migration. Through this sequence of transformations, the desired aporphine core was obtained regioselectively in 75% isolated yield. Since only one regioisomer was produced in the key step of the synthesis, a polar [4+2]-cycloaddition mechanism was proposed. Furthermore, NMR experiments and theoretical calculations were carried out to elucidate the hydrogen migration mechanism. (±)-Apomorphine hydrochloride was achieved after 9 steps in an overall yield of 8% involving benzyne chemistry.

Enhancement of transdermal apomorphine delivery with a diester prodrug strategy

Diester prodrugs of apomorphine, diacetyl apomorphine (DAA), and diisobutyryl apomorphine (DIA) were synthesized, and their partition coefficients, capacity factor (log K′), enzymatic hydrolysis, and in vitro permeation across nude mouse skin were characterized. The lipophilicity of the diesters was between that of apomorphine HCl and the apomorphine base. The prodrugs were chemically stable, but enzymatically unstable in esterase medium, skin homogenate, and human plasma. DAA showed a faster hydrolysis in plasma compared to DIA. Total fluxes (nmol/cm2/h) of the parent drug and prodrug were significantly greater after topical treatment with the diesters in aqueous solutions (water, 30% polyethylene glycol in water, and 30% glycerol in water) compared to treatment with HCl and base forms of apomorphine. DIA flux from deionized water was 51 nmol/cm2/h, which exceeded the flux of apomorphine HCl by 10-fold. The extent of parent drug regeneration after topical application ranged 51-88% and 34-61% for DAA and DIA, respectively, depending on the vehicles selected. Permeation measurements using intact and stratum corneum-stripped skins demonstrated that the viable epidermis/dermis was an important barrier to prodrug permeation. Nano-sized lipid emulsions were also used as carriers for apomorphine and its prodrugs. Diester prodrugs exhibited superior skin permeation compared to the parent drug when formulated into the emulsions. DAA and DIA fluxes from lipid emulsions were 11- and 3-fold higher than that of apomorphine HCl. The results in the present work suggest the feasibility of diester prodrugs for the transdermal delivery of apomorphine.