61-25-6

Basic information

• Product Name: Papaverine hydrochloride
• Synonyms: 6,7-DIMETHOXY-1-VERATRYLISOQUINOLINE HCL;6,7-DIMETHOXY-1-VERATRYL-ISOQUINOLINE HYDROCHLORIDE;6,7-DIMETHOXY-1-(3,4-DIMETHOXYBENZYL)-ISOQUINOLINE HYDROCHLORIDE;1-(3,4-DIMETHOXYBENZYL)-6,7-DIMETHOXYISOQUINOLINE HYDROCHLORIDE;1-[(3',4'-DIMETHOXYPHENYL)METHYL]-6,7-DIMETHOXYISOQUINOLINE HCL;PAPAVERINE HCL;PAPAVERINE HYDROCHLORIDE;1-((3,4-dimethoxyphenyl)methyl)-6,7-dimethoxy-isoquinolinhydrochloride
• CAS NO: 61-25-6
• Molecular Formula: C20H22ClNO4
• Molecular Weight: 375.85
• EINECS: 200-502-1
• Product Categories: Quinoline&Isoquinoline;Alkaloids;Biochemistry;Isoquinoline Alkaloids;Intermediates & Fine Chemicals;Pharmaceuticals;Aromatics;Heterocycles;Inhibitors
• Mol File: 61-25-6.mol

Chemical Properties

• Melting Point: 226°C (dec.)
• Boiling Point: 483.2 °C at 760 mmHg
• Flash Point: 172.2 °C
• Appearance: white/powder
• Vapor Pressure: 5.01E-09mmHg at 25°C
• Storage Temp.: Amber Vial, Refrigerator
• Solubility: H2O: 25 mg/mL
• Water Solubility: freely soluble
• Sensitive: Light Sensitive
• Stability: Stable, but may be light sensitive.
• Merck: 14,7019
• BRN: 3921435
• CAS DataBase Reference: Papaverine hydrochloride(CAS DataBase Reference)
• NIST Chemistry Reference: Papaverine hydrochloride(61-25-6)
• EPA Substance Registry System: Papaverine hydrochloride(61-25-6)

Safety Data

• Hazard Codes: Xn,C,F
• Statements: 22-34-11
• Safety Statements: 22-45-36/37/39-26-16
• RIDADR: UN 1544 6.1/PG 3
• WGK Germany: 1
• RTECS: NW8575000
• F: 8
• TSCA: Yes
• HazardClass: 6.1
• PackingGroup: III
• Hazardous Substances Data: 61-25-6(Hazardous Substances Data)

Usage

Uses

1. Used in Pharmaceutical Industry:
Papaverine hydrochloride is used as an analgesic for the short-term relief of acute renal colic pain, particularly in patients with contraindications for nonsteroidal anti-inflammatory drugs (NSAIDs).
2. Used in Tissue Mechanics Analysis:
Papaverine hydrochloride is used as a vasodilator in oxygenated Krebs solution for the study of tissue mechanics.
3. Used in Tissue Uptake Technique:
It is utilized as a vasodilator in heparinized horse serum for tissue uptake techniques.
4. Used in Neurobiology Research:
Papaverine hydrochloride is used as an inhibitor of H-MPP+ uptake into stably transfected 293 cells expressing either extraneuronal monoamine transporter (EMT) human or EMT rat.
5. Used in Treatment of Erectile Dysfunction:
Papaverine hydrochloride is used as an anti-spasmodic agent in the treatment of erectile dysfunction.
6. Used in Peripheral Vascular Disorders:
Although its use is limited by a lack of potency, papaverine hydrochloride has been utilized in the treatment of peripheral vascular disorders due to its broad antispasmodic action on ACh muscarinic receptors.
Physical Properties:
Papaverine hydrochloride appears as colorless prismatic or acicular crystals with a melting point of 147-148°C. It has a relative density of 1.337 (20/4°C). Papaverine hydrochloride is very soluble in benzene, acetone, hot ethanol, and glacial acetic acid; soluble in concentrated sulfuric acid; slightly soluble in ether, chloroform, and carbon tetrachloride; and insoluble in water. The common crystalline salt is the hydrochloride salt, papaverine hydrochloride.
Chemical Properties:
Papaverine hydrochloride is a crystalline solid that interferes with the mechanism of muscle contraction by inhibiting cyclic nucleotide phosphodiesterases in smooth muscle cells. This inhibition leads to the conversion of cAMP and cyclic guanosine monophosphate (cGMP) to 5'-AMP and 5'-GMP, respectively. The increased levels of cAMP and cGMP are associated with muscle relaxation through their phosphorylation of myosin light-chain kinase.

History

Human beings have a long history of using opium poppy as food and narcotics, which can be dated back to the Neolithic age. The opium, which is the dried product of the opium poppy juice, is widely used as analgesics in the old and new civilizations of the old continent except the Chinese civilization. In 1848, German chemist Georg Merck successfully isolated a new alkaloid from the opium liquor for the first time and named it as “papaverine” . He also determined the correct molecular formula of papaverine as C20 H21NO4 and prepared the papaverine hydrochloride and nitrate by recrystallization method. Then, Goldschmiedt et?al. put forward the molecular structure of papaverine by studying its oxidation products in 1883 and determined the isoquinoline ring as the core structure of papaverine in 1888 . Since the content of papaverine in plants is very low (less than 1%) and can hardly meet the clinical needs, so Pictet and Gams proposed a synthetic method of papaverine in 1909, which makes the large-scale industrialized production of papaverine possible . Study on the pharmacology of papaverine was first published in 1914 by Professor Pal of Vienna, who found that papaverine possessed smooth muscle relaxation effect without causing smooth muscle paralysis and can be used for the treatment of hypertension, angina, and acute uremia .

Indications

Papaverine is mainly used for the treatment of ischemia caused by cerebral, cardiac, and peripheral vascular spasm, as well as visceral spasm of the kidney, gallbladder, or gastrointestinal tract.

Air & Water Reactions

Water soluble.

Reactivity Profile

Papaverine hydrochloride is sensitive to light. .

Health Hazard

SYMPTOMS: Symptoms of exposure to Papaverine hydrochloride may include sleepiness, slowed respiration and slowed heart beat.

Fire Hazard

Flash point data for Papaverine hydrochloride are not available, but Papaverine hydrochloride is probably combustible.

Biochem/physiol Actions

Papaverine is originally used to resolve male impotence.

Pharmacology

As a vasodilator, papaverine is a nonspecific antispasmodic drug of smooth muscle, which is especially effective on pulmonary artery, coronary artery, and great vessels, producing systemic and nonspecific hypotensive and smooth muscle relaxation effect. Papaverine has a direct effect on the smooth muscle cells by inhibiting phosphodiesterase, thus increasing the intracellular concentration of cyclic adenosine monophosphate (cAMP), which further removes the catalase calcium from cytoplasmic of vascular smooth muscle, leading to the direct smooth muscle relaxation without nerve. Papaverine can also inhibit the cardiac conduction, directly act on myocardial cells, and prolong the refractory period. No effect of papaverine on the central nervous system has been found. High dose of papaverine can cause hypotension and tachycardia.

Clinical Use

Papaverine hydrochloride is used for the treatment of ischemia induced by brain, heart, and peripheral vascular spasm, as well as visceral spasm of the kidney, bladder, or gastrointestinal tract. Besides, papaverine is also suitable for angina and arterial embolism, occasionally used for the treatment of erectile dysfunction. In recent years, papaverine hydrochloride also combines with other drugs like nimodipine to treat the vasospasm and crisis triggered by subarachnoid hemorrhage and calculi-induced acute renal colic. The main adverse effects of papaverine include liver function damage, exaggerated respiration induced by rapid parenteral administration, facial flushing, heart rate acceleration, as well as hypotension with vertigo. In addition, overdose of papaverine can lead to blurred vision, diplopia, lethargy, and weakness.

Safety Profile

Poison by ingestion, intraperitoneal, intraduodenal, intravenous, and subcutaneous routes. Human systemic effects: metabolic acidosis, pulse rate increase. An experimental teratogen. Mutation data reported. When heated to decomposition it emits very toxic fumes of NOx and HCl. See also PAPAVERINE

Purification Methods

Recrystallise it from H2O. It sublimes at 140o/0.1mm. Its solubility in H2O is 5%. [Saunders & Srivastava J Pharm Pharmacol 3 78 1951, Biggs Trans Faraday Soc 50 800 1954.] The free base has m 148-150o, The picrate has m 186-189o(dec, 186-186.5o(dec) [Bobbitt J Org Chem 22 1729 1957]. [Beilstein 21 II 202, 21 III/IV 2788, 21/6 V 182.]

InChI:InChI=1/C20H21NO4.ClH/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;1H

Upstream product

• 58-74-2 Papaverine 
• 5884-22-0 1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-3.4-dihydroisoquinoline hydrochloride 
• 93-40-3 (3,4-Dimethoxyphenyl)acetic acid 
• 120-20-7 2-(3,4-dimethoxyphenyl)-ethylamine 
• 6957-27-3 3,4-dihydropapaverine 
• 522-57-6 papaveraldine 
• 139-76-4 N-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)acetamide 

Downstream Products

• 33520-96-6 Bis[1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisochinolin-2-oxid] 
• 522-57-6 papaveraldine 
• 482-76-8 papaverinol 
• 116921-93-8 Demethyl-5 formyl-5 tetrahydro-1,2,3,4 ellipticine 
• 58-74-2 Papaverine 
• 7782-50-5 chlorine 
• 23740-74-1 papaveroline hydrobromide 
• 19716-71-3 N-methylpapaverinium chloride 
• 84030-13-7 N-methyltetrahydropapaveroline hydrobromide 
• 1699-51-0 laudanosine 
• 134204-86-7 4-(10,11-dihdyro-5H-dibenzocyclohepten-5-ylidene)-1-piperidinecarboxylic acid ethyl ester 
• 1605347-69-0 C₂₀H₂₀ClNO₄*C₂HF₃O₂ 
• 893779-75-4 1-(2-chloro-4,5-dimethoxybenzyl)-6,7-dimethoxyisoquinoline 

Relevant articles and documents

Preparation method of papaverine compounds

The invention relates to a preparation method of papaverine compounds. Specifically, the invention relates to a preparation method of a compound as shown in a formula II, and the preparation method comprises a step of reacting a compound as shown in a formula III in the presence of an oxidizing agent. The method is high in yield, mild in reaction condition and suitable for industrial production.

Preparation method of papaverine

The invention discloses a preparation method of papaverine. The invention provides a preparation method of papaverine, which comprises the following steps: (1) in a solvent, in the presence of a cyclization agent, carrying out cyclization reaction as shown in the specification on a compound as shown in a formula I to obtain a compound as shown in a formula II; and (2) in a solvent, in the presence of a dehydrogenation catalyst, carrying out dehydrogenation reaction as shown in the specification on the compound as shown in the formula II to obtain papaverine. The compound as shown in the formula II prepared in the step (1) is directly used in the step (2) without being purified. The method is simple in process, easy to operate, low in cost and suitable for industrial production, and the product is high in yield and purity.

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.

Preparation of powder injection pharmaceutical composition from high-purity papaverine hydrochloride

The invention relates to preparation of a powder injection pharmaceutical composition from high-purity papaverine hydrochloride, in particular to a preparation method of papaverine hydrochloride. Themethod comprises the following steps of: heating 3, 4-dimethoxy-beta-phenyl-ethylamine and 3, 4-dimethoxy-phenyl-acetic acid to melting, and then carrying out reaction in a mixture of benzene and chlorethoxyfos to obtain 6, 7, 3', 4'-tetramethoxy-1-benzyl-dihydro-isoquinoline hydrochloride; then dissolving the wet product in tetrahydronaphthalene after the wet product becomes free alkali, and carrying out dehydrogenation reaction at 180DEG C in the presence of a Raney nickel catalyst; after dehydrogenation is finished, directly filtering the tetrahydronaphthalene reaction mixture from the Raney nickel catalyst into a mixture of a hydrochloric acid aqueous solution and methanol; filtering out precipitates, and performing recrystallizing from the ethanol-water solution in an inert gas environment to obtain off-white 6, 7, 3', 4'-tetramethoxy-1-benzyl isoquinoline hydrochloride, namely papaverine hydrochloride. The invention also relates to a papaverine hydrochloride powder injection pharmaceutical composition, and a preparation method and a quality detection method thereof. The invention achieves excellent technical effects as described in the specification.

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.

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.

1-(α-Aminomethylbenzyl)isoquinoline compounds

Compounds having the structure: SPC1 In which R1 and R2 are alkoxy groups of one to four carbon atoms, R3 and R4 each is hydrogen or an alkoxy group of one to four carbon atoms, and R5 and R6 each is an alkyl group of one to four carbon atoms or an arylalkyl group such as benzyl or R5 taken with R6 and N are pyrrolidinyl, piperidino, or morpholino groups and the pharmaceutically acceptable salts thereof and processes for preparing these compounds. These compounds are useful as vasodilators.