58-74-2

Basic information

• Product Name: PAPAVERINE HYDROCHLORIDE
• Synonyms: Papaverine,99%;18) META CHLORO BENZALDEHYDE;isoquinoline, 1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethox;Papacon;Papalease;Papanerin-HCl [German];Papaveri;PAPAVERINE
• CAS NO: 58-74-2
• Molecular Formula: C₂₀H₂₁NO₄
• Molecular Weight: 375.85
• EINECS: 200-502-1
• Mol File: 58-74-2.mol

Chemical Properties

• Melting Point: 226 °C
• Boiling Point: 475.36°C (rough estimate)
• Flash Point: 172.2°C
• Appearance: white/powder
• Density: d420 1.337
• Refractive Index: 1.6250 (estimate)
• Solubility: H2O: 25 mg/mL
• PKA: 6.4(at 25℃)
• Water Solubility: 37.33mg/L(37.5 oC)
• Merck: 14,7019
• BRN: 312930
• CAS DataBase Reference: PAPAVERINE HYDROCHLORIDE(CAS DataBase Reference)
• NIST Chemistry Reference: PAPAVERINE HYDROCHLORIDE(58-74-2)
• EPA Substance Registry System: PAPAVERINE HYDROCHLORIDE(58-74-2)

Safety Data

• Hazard Codes: Xn
• Statements: 22
• Safety Statements: 22
• RIDADR: UN 1544 6.1/PG 3
• WGK Germany: 1
• RTECS: NW8575000
• F: 8
• HazardClass: 6.1(a)
• PackingGroup: II
• Hazardous Substances Data: 58-74-2(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Papaverine Hydrochloride is used as a smooth muscle relaxant for its vasodilator action on the blood vessels in the brain. It is particularly effective against asthma and is also utilized as a treatment for various conditions involving smooth muscle constriction.
Used in Veterinary Medicine:
In the veterinary industry, Papaverine Hydrochloride serves as a coccidiostat, which is a substance used to prevent or treat coccidiosis, a disease caused by protozoan parasites in animals.
Used in Folic Acid Metabolism Inhibition:
Papaverine Hydrochloride acts as a folate metabolic inhibitor, playing a role in the regulation of folic acid metabolism, which is essential for various cellular processes, including DNA synthesis and repair.
Used in Research and Development:
As an opium alkaloid, Papaverine Hydrochloride is also used in research and development for studying its effects on smooth muscle relaxation and vasodilation, as well as its potential applications in the development of new drugs and therapies.
Brand Name:
Pavabid (Hoechst Marion Roussel) is a brand name under which Papaverine Hydrochloride is marketed.

Originator

Lempav Ty-Med ,Lemmon,US,1975

Indications

Papaverine (Pavabid) is a nonspecific phosphodiesterase inhibitor that increases cAMP and cGMP levels in penile erectile tissue. Papaverine is particularly known as a smooth muscle relaxant and vasodilator. Its principal pharmacological action is as a nonspecific vasodilator of smooth muscles of the arterioles and capillaries. Various vascular beds and smooth muscle respond differently to papaverine administration both in intensity and duration. Papaverine decreases the resistance to arterial inflow and increases the resistance to venous outflow.

Manufacturing Process

To 3.65 g (0.01 mol) of monohydrated adenosine-5'-monophosphoric acid, brought into suspension in a mixture of 45 ml of water and 5 ml of ethanol, are added 339 g (0.01 mol) of papaverine base (melting point, 147°C). The mixture is gently heated until a final temperature of 40°C is reached. The solution obtained is then filtered and the filtrate is concentrated under vacuum. The remaining product quickly crystallizes. After drying to 50°C to constant weight, there are obtained 6.68 g of desired product, in the monohydrated state, as a white crystalline powder, which melts at 140°C and is very soluble in water.

Therapeutic Function

Vasodilator, Platelet aggregation inhibitor

Health Hazard

Papaverine is an inhibitor of cyclic nucleotidephosphodiesterase, producing vasodilatoryeffect. The acute toxic effects relative tophenanthrene-type opium alkaloids (e.g.,morphine, heroin) are low and the symptomsare not the same. Papaverine is neither a narcoticnor an addictive substance. Excessivedoses may produce drowsiness, headache,facial flushing, constipation, nausea, vomiting,and liver toxicity.The LD50 data reported in the literatureshow variation. An oral LD50 value in rats ison the order of 400 mg/kg.

Mechanism of action

When administered by intracavernosal injection, papaverine, a weak and nonspecific PDE inhibitor, is thought to cause relaxation of the cavernous smooth muscles and vasodilation of the penile arteries by inhibition of PDE. These effects result in increased arterial blood flow into the corpus cavernosa and in swelling and elongation of the penis. Venous outflow also is reduced, possibly as a result of increased venous resistance.

Clinical Use

Papaverine is highly effective in men with psychogenic and neurogenic ED but less effective in men with vasculogenic ED. Papaverine–phentolamine combinations have been used in self-injection procedures. Papaverine doses may range from 15 to 60 mg. Papaverine treatment in patients with severe arterial or venous incompetence is usually unsuccessful, but autoinjections using low doses sufficient to achieve an erection are safe and efficient.

Side effects

Major side effects associated with papaverine therapy include priapism, corporeal fibrosis, and occasional increases in serum aminotransferases. Intracorporeal scarring may be related to the low pH of the vehicle that is necessary to solubilize papaverine.Attempts to buffer papaverine to render it more suitable for intracavernosal injection have not been entirely satisfactory, and such delivery may still lead to intracorporeal scarring.

Safety Profile

Poison by ingestion, intramuscular, subcutaneous, intradermal, intraperitoneal, and intravenous routes. Human systemic effects: coma, somnolence. Its central nervous system action is about midway between those of morphme and codeine, and large doses do not produce the amount of excitement caused by codeine or the soporific action of morphine. Mutation data reported. A cerebral vasodilator and smooth muscle relaxant. Combustible when exposed to heat or flame. When heated to decomposition it emits toxic fumes of NOx. See also MORPHINE.

Synthesis

Papaverine, 1-veratryl-6,7-dimethoxyisoquinolin (19.4.7), is synthesized from veratrol. Veratrol undergoes chloromethylation, forming 3,4-dimethoxybenzylchloride (19.4.1). Reacting this with potassium cyanide gives 3,4-dimethoxybenzylcyanide (19.4.2). The resulting 3,4-dimethoxybenzylcyanide undergoes reduction by hydrogen over Raney nickel, forming homoveratrylamine (19.4.3). At the same time 3,4-dimethoxybenzylcyanide (19.4.2) undergoes acidic hydrolysis giving 3,4-dimethoxyphenylacetic acid (19.4.4). The interaction of the resulting compounds brings to corresponding amide (19.4.5). The cyclization of this by Bischler–Napieralski method, using phosphorous oxychloride, gives 3,4-dihydropapaverine (19.4.6), which is dehydrated into the desired papverine when heated in tetraline at high temperatures.

InChI:InChI=1/C20H21NO4/c1-22-17-6-5-13(10-18(17)23-2)9-16-15-12-20(25-4)19(24-3)11-14(15)7-8-21-16/h5-8,10-12H,9H2,1-4H3

Upstream product

• 6957-27-3 3,4-dihydropapaverine 
• 522-57-6 papaveraldine 
• 91790-53-3 1,2,3,4-tetrahydro-6,7-dimethoxy-2-(3,4-dimethoxybenzyl)isoquinoline 
• 78004-24-7 (3,4-dimethoxy-phenyl)-acetic acid-(β-hydroxy-3,4-dimethoxy-phenethylamide) 
• 861056-23-7 (3,4-dimethoxy-phenyl)-acetic acid-(3,4,β-trimethoxy-phenethylamide) 
• 102449-80-9 6,7-dimethoxy-1-veratryl-3,4-dihydro-isoquinoline-3-carboxylic acid 
• 60-18-4 L-tyrosine 
• 482-76-8 papaverinol 
• 186581-53-3 diazomethane 
• 57231-35-3 4',6-O,O-dimethylpapaveroline 
• 73168-84-0 1-(2-iodo-4,5-dimethoxybenzyl)-6,7-dimethoxyisoquinoline 
• 33520-96-6 Bis[1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisochinolin-2-oxid] 
• 51449-10-6 1-(2'-bromo-4',5'-dimethoxybenzyl)-6,7-dimethoxyisoquinoline 
• 2679-26-7 2-Methylpapaverinium iodide 

Downstream Products

• 2863-95-8 papaverine ethiodide 
• 482-76-8 papaverinol 
• 89383-97-1 6,7-dimethoxy-2-methyl-1-veratryl-isoquinolinium; methyl sulfate 
• 2679-26-7 2-Methylpapaverinium iodide 
• 522-57-6 papaveraldine 
• 494-99-5 1,2-dimethoxy-4-methylbenzene 
• 577-68-4 m-hemipinic acid 
• 574-77-6 Papaveroline 
• 51449-10-6 1-(2'-bromo-4',5'-dimethoxybenzyl)-6,7-dimethoxyisoquinoline 
• 25944-25-6 1-(4,5-dimethoxy-2-nitrobenzyl)-6,7-dimethoxyisoquinoline 

Relevant articles and documents

Photochemistry and photophysics of papaverine N-oxide

The photochemistry and photophysics of papaverine N-oxide in polar aprotic and protic solvents has been studied in detail. Complex energy and charge-transfer phenomena between chromophores occur in papaverine. New photochemistry for the papaverine N-oxide system is reported. Irradiation in protic media results in the formation of an emissive charge-transfer state with ensuing intramolecular hydroxylation in high isolated yields (75-80%).

Efficient Photoinduced Electron Transfer in Papaverine N-Oxide: Regioselective Intramolecular Hydroxylation of Papaverine as an Alternative Disconnection for the Synthesis of Cularine Alkaloids

The photochemistry of papaverine N-oxide in polar aprotic and protic solvents has been studied in detail.Complex energy and charge transfer phenomena between chromophores occur in papaverine.Irradiation in protic media results in the formation of an emissive charge transfer state with concomitant intramolecular hydroxylation.

Green Technology for Salt Formation: Slurry Reactive Crystallization Studies for Papaverine HCl and 1:1 Haloperidol-Maleic Acid Salt

Papaverine HCl was successfully suspended by slurry reactive crystallization with the use of isopropyl alcohol (IPA) at 25 °C, a solid-to-liquid ratio of 0.19 g/mL, an aging time of 8 h, a yield of 82.0 w/w %, crystal sizes of 200-400 μm, and the value for enthalpy of fusion of 154.5 J/g. The poor solubility of papaverine in IPA and better solubility of papaverine HCl in water-containing IPA had made the homogeneous nucleation of papaverine HCl dominate. Crystal size and crystallinity of papaverine HCl were time and temperature dependent. However, the 1:1 haloperidol-maleic acid salt was also successfully suspended and generated by slurry reactive crystallization with the use of water at 25 °C, a solid-to-liquid ratio of 0.18 g/mL, an aging time of 8 h, a yield of 82.0 w/w %, crystal sizes of 500-1000 μm, and the value for enthalpy of fusion of 84.9 J/g. The poor solubility of haloperidol and 1:1 haloperidol-maleic acid salt in water had made the heterogeneous nucleation of 1:1 haloperidol-maleic acid salt dominate. Crystal size and crystallinity of 1:1 haloperidol-maleic acid salt became less sensitive to time and temperature. Comparing with grinding, solution reactive crystallization by cooling, and solution recrystallization by cooling, slurry reactive crystallization was a simple, robust, straightforward, low-constant-temperature, low-solvent-volume, and environmentally benign process giving comparable yield, particle size distribution, and crystallinity. Moreover, the use of a poor solvent in the slurry reactive crystallization enabled the recycling of the mother liquor without any significant loss in yield and crystallinity up to three cycles.

Easy access to drug building-blocks through benzylic C-H functionalization of phenolic ethers by photoredox catalysis

A visible light-mediated photocatalyzed C-C-bond forming method for the benzylic C-H functionalization of phenolether containing synthetic building blocks based on a radical-cation/deprotonation strategy is reported. This method allows the mild, selective generation of benzyl radicals in phenolic complex molecules and drug-like compounds, providing new entries in synthetic and medicinal chemistry.

1,2,3-Triazole-Mediated Synthesis of 1-Methyleneisoquinolines: A Three-Step Synthesis of Papaverine and Analogues

A metal-free three-step synthesis toward functionalized 1-methyleneisoquinolines from readily available substrates is reported. First, acetal-containing 1,2,3-triazoles were prepared via a high-yielding triazolization reaction and quantitatively converted into triazolo[5,1-a]isoquinolines. Next, the acid-promoted ring opening of these fused triazoles was studied in order to obtain coupling to a diverse scope of nucleophiles, including carbon nucleophiles such as veratrole. By means of non-nucleophilic strong acids under anhydrous conditions, a series of unprecedented isoquinolines and imidazo[5,1-a]isoquinolines was synthesized.

One-Pot Synthesis of Papaverine Hydrochloride and Identification of Impurities

Abstract: A one-pot synthesis of papaverine hydrochloride with 99.6% purity was performed using xylene as solvent for the entire process. The critical parameters of each step, as well as the impurities generated, were identified. The overall yield was improved to 63%. The proposed synthetic procedure is suitable for industrial production.

Reaction of papaverine with Baran Diversinates

The reaction of papaverine with a series of Baran Diversinates is reported. Although the yields were low, it was possible to synthesize a small biodiscovery library using this plant alkaloid as a scaffold for late-stage C–H functionalization. Ten papaverine analogues (2–11), including seven new compounds, were synthesized. An unexpected radical-induced exchange reaction is reported where the dimethoxybenzyl group of papaverine was replaced by an alkyl group. This side reaction enabled the synthesis of additional novel fragments based on the isoquinoline scaffold, which is present in numerous natural products. Possible reasons for the poor yields in the Diversinate reactions with this particular scaffold are discussed.

Ruthenium-Mediated Dual Catalytic Reactions of Isoquinoline via C?H Activation and Dearomatization for Isoquinolone

We have unraveled the ruthenium-promoted prototype reaction based on C(sp2)?C(sp3) bond formation through the reigoselective C?H activation of isoquinoline and pyridine derivatives with various alkyl halides, leading to 1-substituted isoquinoline products in good yield. This C?H catalytic reaction did not rely on chelation assistance of the directing group of the substrates. The dimer [RuCl2(p-cymene)]2in combination with an N-heterocyclic carbene ligand, adamantanecarboxylic acid and K2CO3base in N-methyl-2-pyrrolidone solution at 150 °C are the best conditions. Simultaneously, we are also able to chemically tune the reaction mode to dearomatization by adding water, leading to isoquinolone products. This reaction methodology is not suitable for other nitrogen-containing heteroarenes such as pyridazines and pyrimidines. (Figure presented.).

Preparation methods of papaverine and papaverine hydrochloride

The invention discloses a preparation method of papaverine. The preparation method comprises 1, dissolving 3, 4-dihydropapaverine hydrochloride in water and adjusting pH of the solution to greater than 7, 2, through trimethylbenzene, carrying out extraction on the aqueous solution obtained through the step 1, and 3, adding a dehydrogenation reaction catalyst into the obtained organic phase, carrying out a dehydrogenation reaction process at a temperature of 50-180 DEG C and then treating the product to obtain papaverine. The invention also discloses a method for preparing papaverine hydrochloride from the papaverine. Through use of trimethylbenzene as a dehydrogenation reaction solvent, a dehydrogenation reaction temperature is reduced, peroxide production is avoided and production safety is greatly improved. The preparation method realizes recycle of trimethylbenzene and reduces a production cost of papaverine or papaverine hydrochloride.

C1-Benzyl and benzoyl isoquinoline synthesis through direct oxidative cross-dehydrogenative coupling with methyl arenes

An oxidative cross-dehydrogenative coupling (CDC) of isoquinolines with methyl arenes has been developed, allowing for the facile synthesis of a broad range of structurally diverse C1-benzyl and -benzoyl isoquinolines. The direct use of readily available methyl arenes as coupling partners avoids unproductive steps for preactivating the functional group installation, and is therefore attractive. The method exhibits excellent chemoselectivity, affording exclusive benzylated products in the presence of DTBP and a catalytic amount of Y(OTf)3, and yielding benzoylated ones with TBHP and a catalytic amount of MnO2.