66357-35-5

Usage

Uses

Used in Pharmaceutical Industry:
Ranitidine hydrochloride is used as a therapeutic agent for treating stomach and duodenum ulcers, as well as other conditions accompanied by elevated acidity of the gastrointestinal tract. It works by reducing pepsin activity and blocking histamine H2 receptors, which helps in decreasing the production of stomach acid.
Used in Research:
Ranitidine (CAS# 66357-35-5) is used as a standard for testing the therapeutic effect of various treatments, such as brown propolis extract, against aspirin and ethanol-induced gastric ulcers. This helps in evaluating the efficacy of new treatments in comparison to the established effects of ranitidine.
Synonyms:
Ranitidine hydrochloride is also known by various other names, including zantac, azantac, raniplex, ranidil, and others.

Indications

Ranitidine (Zantac) is another H2 receptor antagonist that does not have the same antiandrogen side effects as cimetidine. Note that both cimetidine and ranitidine inhibit the cytochrome P-450 microsomal enzyme system.

Biological Activity

Potent, selective and competitive histamine H 2 receptor antagonist (pA 2 = 6.95-7.2). In vivo, inhibits gastric acid secretion induced by histamine, pentagastrin, bethanecol and food. Also inhibits aspirin-induced gastric lesions.

Clinical Use

H2 antagonist: Conditions associated with hyperacidity

Synthesis

Ranitidine, N[2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]- N′-methyl-2-nitro-1,1-ethendiamine (16.2.8), is synthesized from furfuryl alcohol, which undergoes aminomethylation reaction using dimethylamine and paraform, which form 5- (dimethylaminomethyl)furfuryl alcohol (16.2.6). Further reaction with 2-mercaptoethylamine hydrochloride gives a product of substitution of the hydroxyl group in (16.2.6), 5-dimethylaminomethyl-2-(2′-aminoethyl)thiomethylfurane (16.2.7). Reacting this with Nmethyl- 1-methylthio-2-nitroethenaamine gives ranitidine (16.2.8).

Drug interactions

Potentially hazardous interactions with other drugs Alpha-blockers: effects of tolazoline antagonised. Antifungals: absorption of itraconazole and ketoconazole reduced; concentration of posaconazole possibly reduced - avoid. Antivirals: concentration of atazanavir reduced; concentration of raltegravir possibly increased - avoid; avoid for 12 hours before and 4 hours after rilpivirine. Ciclosporin: may increase or not change ciclosporin levels; nephrotoxicity, additive hepatotoxicity and thrombocytopenia reported. Cytotoxics: reduced gefitinib concentration; reduces concentration of erlotinib and possibly pazopanib, give at least 2 hours before or 10 hours after ranitidine; absorption of dasatinib reduced - avoid; possibly reduced absorption of lapatinib. Ulipristal: contraceptive effect possibly reduced - avoid with high dose ulipristal.

Metabolism

Ranitidine is not extensively metabolised. A small proportion of ranitidine is metabolised in the liver to the N-oxide, the S-oxide, and desmethylranitidine; the N-oxide is the major metabolite but accounts for only about 4-6% of a dose. The fraction of the dose recovered as metabolites is similar after both oral and IV dosing; and includes 6% of the dose in urine as the N-oxide, 2% as the S-oxide, 2% as desmethylranitidine and 1-2% as the furoic acid analogue. There is also some excretion in the faeces.

Dosage forms

150 mg b.i.d.

InChI:InChI=1/C13H22N4O3S/c1-14-13(9-17(18)19)15-6-7-21-10-12-5-4-11(20-12)8-16(2)3/h4-5,9,14-15H,6-8,10H2,1-3H3/b13-9+

Synthetic route

(E-)-N-methyl-1-(methylthio)-2-nitroethanamine (61832-41-5) + 5-{[(2-aminoethyl)thio]methyl}-N,N-dimethyl-2-furfurylamine (66356-53-4) → Ranitidine (66357-35-5)

Conditions	Yield
In water at 55℃;	92%

1,1-dichloro-2-nitro ethylene (6061-04-7) + 2-mercaptoethylamine hydrochloride (156-57-0) + 5-(N,N'-dimethylaminomethyl)-2-chloromethyl-furan + methylamine (74-89-5) → Ranitidine (66357-35-5)

Conditions	Yield
Stage #1: 1,1-dichloro-2-nitro ethylene; 2-mercaptoethylamine hydrochloride With sodium hydroxide at 50℃; for 1h; Stage #2: methylamine With calcium oxide In ethanol at 20℃; for 12h; Stage #3: 5-(N,N'-dimethylaminomethyl)-2-chloromethyl-furan In ethanol; water at 45℃; for 2h; Temperature;	90%

(Z)-1-β-hydroxyethylamino-1-methylamino-2-nitroethene + 5-(N,N-dimethylaminomethyl)-2-thiomethylfuran hydrobromide → Ranitidine (66357-35-5)

Conditions	Yield
Stage #1: (Z)-1-β-hydroxyethylamino-1-methylamino-2-nitroethene; 5-(N,N-dimethylaminomethyl)-2-thiomethylfuran hydrobromide With hydrogenchloride at 0℃; for 40h; Stage #2: With sodium hydroxide; sodium chloride at 0℃; pH=9;	17.3%

nitromethane (75-52-5) + N-methyl-N'-(2-<(5-dimethylaminomethyl)-furan-2-ylmethylthio>-ethyl)-carbodiimide (91756-97-7) → Ranitidine (66357-35-5)

Conditions	Yield
With sodium hydride 1.) DMF, 30 min, room temp., 2.) DMF, 90 min; Yield given. Multistep reaction;

N,N-dimethylammonium chloride (506-59-2) + 5-[2-((E)-1-Methylamino-2-nitro-vinylamino)-ethylsulfanylmethyl]-furan-2-carbaldehyde → Ranitidine (66357-35-5) + N-[2-[[[5-(hydroxymethyl)-2-furanyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine

Conditions	Yield
With sodium acetate; sodium cyanoborohydride In methanol 1) -70 deg C, 3 h, 2) -18 deg C; Yield given;

N-methyl-N'-(2-<(5-dimethylaminomethyl)-furan-2-ylmethylthio>-ethyl)-urea (66357-07-1) → Ranitidine (66357-35-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 52 percent / (C6H5)3PBr2, (C2H5)3N / CH2Cl2 / 2 h 2: 1.) NaH / 1.) DMF, 30 min, room temp., 2.) DMF, 90 min View Scheme

2-(nitromethylene)thiazolidine (94662-61-0) + 4-methyl-2-pentanone (108-10-1) + 5-chloromethyl-2-furfuryldimethylamine hydrochloride → Ranitidine (66357-35-5)

Conditions	Yield
With methylamine In acetonitrile

2-(nitromethylene)thiazolidine (94662-61-0) + 5-chloromethyl-2-furfuryldimethylamine hydrochloride → Ranitidine (66357-35-5)

Conditions	Yield
With sodium hydroxide; methylamine In water; isopropyl alcohol
With sodium acetate; potassium carbonate; methylamine In 4-methyl-2-pentanone; acetonitrile

N-[2-[[5-(1,3-dioxolan-2-yl)-2-furanylmethyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine + N,N-dimethylammonium chloride (506-59-2) + pyrographite (7440-44-0) → Ranitidine (66357-35-5)

Conditions	Yield
With hydrogenchloride; ammonia; sodium cyanoborohydride; sodium carbonate; acetic acid; dimethyl amine In tetrahydrofuran; methanol; ethanol; water

N-(2-chloroethyl)-N'-methyl-2-nitro-1,1-ethenediamine + 5-[(Dimethylamino)methyl]-2-furanmethanethiol, oxalate + pyrographite (7440-44-0) → Ranitidine (66357-35-5)

Conditions	Yield
With potassium carbonate In tetrahydrofuran; ethanol; water

1,4-dioxane (123-91-1) + methanol-0.88 ammonia + N-[2-[[5-(1,3-dioxolan-2-yl)-2-furanylmethyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine + N,N-dimethylammonium chloride (506-59-2) → Ranitidine (66357-35-5)

Conditions	Yield
With hydrogenchloride; sodium cyanoborohydride; sodium carbonate; acetic acid; dimethyl amine In tetrahydrofuran; water; 4-methyl-2-pentanone; acetone

N-[2-[[5-(1,3-dioxolan-2-yl)-2-furanylmethyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine + N,N-dimethylammonium chloride (506-59-2) → Ranitidine (66357-35-5)

Conditions	Yield
With hydrogenchloride; sodium borohydrid; sodium carbonate; dimethyl amine In tetrahydrofuran; ethanol; water
With hydrogenchloride; ammonia; sodium cyanoborohydride; sodium carbonate; dimethyl amine In tetrahydrofuran; ethanol; dichloromethane; Isopropyl acetate; water; acetic acid

(5-dimethylaminomethyl-furan-2-yl)-methanol (15433-79-1) + methanol-0.88 ammonia + N,N'-bis-[Thio(2,1-ethanediyl)]bis(N'-methyl-2-nitro-1,1-ethenediamine) → Ranitidine (66357-35-5)

Conditions	Yield
With sodium carbonate In tetrahydrofuran; hydrogenchloride

ethyleneimine (151-56-4) + 1-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio]-N-methyl-2-nitroethenamine → Ranitidine (66357-35-5)

Conditions	Yield
In water; 4-methyl-2-pentanone

N-[2-[[5-(1,3-dioxolan-2-yl)-2-furanylmethyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine → Ranitidine (66357-35-5)

Conditions	Yield
With hydrogenchloride; sodium borohydrid; ammonia; acetic acid; dimethyl amine In tetrahydrofuran; ethanol

N-(2-chloroethyl)-N'-methyl-2-nitro-1,1-ethenediamine + 1-[[[5-[(Dimethylamino)methyl]-2-furanyl]methyl]thio]methanimidamide, maleate → Ranitidine (66357-35-5)

Conditions	Yield
With potassium carbonate In tetrahydrofuran; water; magnesium sulfate
With potassium hydroxide; sodium carbonate In tetrahydrofuran; water

N-(2-chloroethyl)-N'-methyl-2-nitro-1,1-ethenediamine + 5-[(Dimethylamino)methyl]-2-furanmethanethiol, oxalate → Ranitidine (66357-35-5)

Conditions	Yield
With potassium hydroxide In tetrahydrofuran; water; 4-methyl-2-pentanone

5-{[(2-aminoethyl)thio]methyl}-N,N-dimethyl-2-furfurylamine (66356-53-4) + pyrographite (7440-44-0) + 1,1-di(methylsulfanyl)-2-nitroethylene (13623-94-4) → Ranitidine (66357-35-5)

Conditions	Yield
In methanol; methanolic methylamine; acetonitrile

(5-dimethylaminomethyl-furan-2-yl)-methanol (15433-79-1) + N-(2-mercaptoethyl)-N'-methyl-2-nitro-1,1-ethenediamine → Ranitidine (66357-35-5)

Conditions	Yield
In hydrogenchloride

(furan-2-ylmethyl)dimethylamine (14496-34-5) + N-(2-mercaptoethyl)-N'-methyl-2-nitro-1,1-ethenediamine → Ranitidine (66357-35-5)

Conditions	Yield
With paraformaldehyde In hydrogenchloride; acetic acid

5-hydroxymethyl-2-furfuraldehyde (67-47-0) → Ranitidine (66357-35-5)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: hydrogenchloride / dichloromethane / 20 °C 2.1: sodium hydride / tetrahydrofuran / 0.5 h / Inert atmosphere 2.2: 20 °C / Inert atmosphere 3.1: methanol / 0.67 h / 20 °C 3.2: 0.33 h / 0 °C 4.1: water / 2.5 h / Reflux; Alkaline conditions 5.1: water / 55 °C View Scheme

5-chloromethylfurfural (1623-88-7) → Ranitidine (66357-35-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium hydride / tetrahydrofuran / 0.5 h / Inert atmosphere 1.2: 20 °C / Inert atmosphere 2.1: methanol / 0.67 h / 20 °C 2.2: 0.33 h / 0 °C 3.1: water / 2.5 h / Reflux; Alkaline conditions 4.1: water / 55 °C View Scheme

5-[[(2-acetamidoethyl)thio]methyl]furfural (1350914-20-3) → Ranitidine (66357-35-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: methanol / 0.67 h / 20 °C 1.2: 0.33 h / 0 °C 2.1: water / 2.5 h / Reflux; Alkaline conditions 3.1: water / 55 °C View Scheme

5-[[(2-acetamidoethyl)thio]methyl]-N,N-dimethyl-2-furanmethanamine (79589-16-5) → Ranitidine (66357-35-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: water / 2.5 h / Reflux; Alkaline conditions 2: water / 55 °C View Scheme

D-fructose (470-23-5, 470-24-6, 10247-46-8, 10489-79-9, 35673-97-3, 36441-90-4, 36441-92-6, 36468-68-5, 37500-17-7, 40461-86-7, 40461-87-8, 41579-20-8, 41846-98-4, 41846-99-5, 41847-00-1, 41847-01-2, 41847-02-3, 41847-03-4, 41847-04-5, 41847-05-6, 41847-06-7, 41847-51-2, 41847-52-3, 42744-42-3) → Ranitidine (66357-35-5)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: 1-butyl-3-methylimidazolium chloride; sulfuric acid / 60 °C 2.1: hydrogenchloride / dichloromethane / 20 °C 3.1: sodium hydride / tetrahydrofuran / 0.5 h / Inert atmosphere 3.2: 20 °C / Inert atmosphere 4.1: methanol / 0.67 h / 20 °C 4.2: 0.33 h / 0 °C 5.1: water / 2.5 h / Reflux; Alkaline conditions 6.1: water / 55 °C View Scheme

Ranitidine (66357-35-5) → ranitidine hydrochloride (66357-59-3, 71130-06-8)

Conditions	Yield
With hydrogenchloride In ethanol at 0℃; pH=4.5 - 6.5; Temperature; pH-value;	93.84%
With hydrogenchloride for 2.03333h;

Ranitidine (66357-35-5) + atorvastatin (134523-00-5) → atorvastatin; ranitidine salt

Conditions	Yield
In ethyl acetate Product distribution / selectivity;
In methanol; 2-methylpropyl acetate Product distribution / selectivity;

ibuprofen (15687-27-1) + Ranitidine (66357-35-5) → ranitidinium ibuprofenate

Conditions	Yield
In acetone at 25℃; for 24h;

Upstream product

• 506-59-2 N,N-dimethylammonium chloride 
• 94662-61-0 2-(nitromethylene)thiazolidine 
• 108-10-1 4-methyl-2-pentanone 
• 15433-79-1 (5-dimethylaminomethyl-furan-2-yl)-methanol 
• 66356-53-4 5-{[(2-aminoethyl)thio]methyl}-N,N-dimethyl-2-furfurylamine 
• 7440-44-0 pyrographite 
• 13623-94-4 1,1-di(methylsulfanyl)-2-nitroethylene 
• 6061-04-7 1,1-dichloro-2-nitro ethylene 
• 156-57-0 2-mercaptoethylamine hydrochloride 
• 74-89-5 methylamine 
• 1623-88-7 5-chloromethylfurfural 
• 1350914-20-3 5-[[(2-acetamidoethyl)thio]methyl]furfural 
• 102721-76-6 2-methylamino-2-methylthio-1-nitroethene 
• 66357-35-5 ranitidine 

Downstream Products

• 66357-35-5 ranitidine hydrochloride 
• 73857-20-2 C₁₃H₂₂N₄O₄S 
• 73851-70-4 Ranitidine S-oxide 
• 72078-82-1 N-methylnitroacetamide 
• 66356-53-4 5-{[(2-aminoethyl)thio]methyl}-N,N-dimethyl-2-furfurylamine 
• 74-89-5 methylamine 
• 81074-81-9 5-[(dimethylamino)methyl]-furfuryl alcohol hydrochloride 
• 15433-79-1 (5-dimethylaminomethyl-furan-2-yl)-methanol 
• 112233-24-6 3-methylamino-5,6-dihydro-2H-thiazin-2-one O-5-dimethylaminomethylfurfuryloxime 
• 112233-23-5 3-methylamino-5,6-dihydro-2H-1,4-thiazin-2-one oxime hydrochloride 
• 112233-25-7 N,N-dimethyl-5-(2(1-methylamino-2-(5-dimethylaminomethyl-2-furfuryl)-2-nitrovinylamino)ethyl-thiomethyl)furfurylamine 
• 124-38-9 carbon dioxide 
• 73851-70-4 Ranitidine S-oxide 
• 66357-59-3 ranitidine hydrochloride 

Relevant academic research and scientific papers

An improved synthesis of the antiulcer drug ranitidine from N-[2-[[[5- (hydroxymethyl)-2-furanyl]-methyl]-thio]-ethyl]-N'-methyl-2-nitro-1,1- ethenediamine

An improved synthesis of the antiulcer drug ranitidine from N-[2-[[[5- (hydroxymethyl)-2-furanyl]-methyl]-thiol]-ethyl]-N'methyl-2-nitro-1,1- ethenediamine is reported.

Ranitidine oral preparation for treating new indications of erosive esophagitis

The invention discloses a ranitidine and a preparation method thereof, as well as a ranitidine preparation, a compound preparation and a preparation method thereof. The ranitidine has a low impurity content, high stability, and the preparation method is simple; the ranitidine preparation and the compound preparation prepared therefrom have high bioavailability and safety. The ranitidine, the ranitidine preparation and the compound preparation provided by the invention can effectively treat and maintain the treatment of erosive esophagitis.

New method for synthesizing ranitidine

The invention discloses a new method for synthesizing ranitidine. The method comprises the steps of synthesizing vinylidene chloride, synthesizing 1, 1-dichloro-2-nitroethylene, carrying out a ring-closing reaction, carrying out a ring-opening reaction in presence of a desiccant, and synthesizing the ranitidine. The method adopts an anhydrous environment in the preparation process of a ring-opening product, thus avoiding the interference with the reaction and the generation of impurities due to the presence of water, reducing the post-treatment work and increasing the utilization rate of the raw materials. The preparation method provided by the invention effectively increases the reaction yield of the ring-opening product, improves the purity of the ring-opening reaction, and reduces the reaction time; therefore, the yield and purity of the product ranitidine are improved, the production cost is lowered, and the method is more beneficial to industrial production.

Novel synthesis method for high-stability ranitidine bismuth citrate

The invention discloses a novel synthesis method for high-stability ranitidine bismuth citrate. The method includes the steps of: 1) preparing a raw material solution; 2) performing a reaction to prepare ranitidine; 3) purifying the ranitidine; 4) performing a salt forming reaction; 5) discolorizing and sterilizing a product; and 6) producing a ranitidine bismuth citrate finish product. The novel synthesis method, through reasonable process design, can increase the quality and stability of ranitidine, thereby improving the pharmacologic property and stability of the ranitidine bismuth citrate. The novel synthesis method is low in raw material cost, has gentle process conditions, is good in controllability and yield, and is suitable for industrial production.

Critical Influence of 5-Hydroxymethylfurfural Aging and Decomposition on the Utility of Biomass Conversion in Organic Synthesis

Spectral studies revealed the presence of a specific arrangement of 5-hydroxymethylfurfural (5-HMF) molecules in solution as a result of a hydrogen–bonding network, and this arrangement readily facilitates the aging of 5-HMF. Deterioration of the quality of this platform chemical limits its practical applications, especially in synthesis/pharma areas. The model drug Ranitidine (Zantac) was synthesized with only 15 % yield starting from 5-HMF which was isolated and stored as an oil after a biomass conversion process. In contrast, a much higher yield of 65 % was obtained by using 5-HMF isolated in crystalline state from an optimized biomass conversion process. The molecular mechanisms responsible for 5-HMF decomposition in solution were established by NMR and ESI-MS studies. A highly selective synthesis of a 5-HMF derivative from glucose was achieved using a protecting group at O(6) position.

Synthesis of ranitidine (Zantac) from cellulose-derived 5-(chloromethyl)furfural

The biomass-derived platform chemical 5-(chloromethyl)furfural is converted into the blockbuster antiulcer drug ranitidine (Zantac) in four steps with an overall 68% isolated yield. The Royal Society of Chemistry.

ANHYDROUS TABLET OF RANITIDINE HYDROCHLORIDE WITH DOUBLE-LAYER COATING AND ITS COMPOSITION

The invention concerns an anhydrous tablet containing anhydrous ranitidine hydrochloride, coated by a double-layer coating, its composition and the relevant process of preparation. The anhydrous tablet of the invention is characterized by the direct dry tabletting, without using water, of a mixture consisting of the active ingredient anhydrous ranitidine hydrochloride, in the crystalline form "allomorphous Form 1" having a particular purity and stability, and by a global amount of other excipients and adjuvant substances or inert vehicles less than the weight of the active ingredient. Moreover, the anhydrous tablet of the invention is characterized by a high percentage of disintegrating substance in the tabletting mixture and by a special two-layer coating.

PROCESS FOR PRODUCTION OF ALKANESULFONIC ACID

The present invention relates to a process for the production of alkanesulfonic acid. More particularly, the present invention relates to a process for the production of alkanesulfonic acid from alkyl mercaptan effluents generated in chemical industries. The process of the invention comprises the oxidation of the entire alkyl mercaptan generated as an effluent in the chemical industries to serve two concomitant purposes: (1) complete removal of obnoxious odour, and (2) value addition by the production of alkanesulfonic acids selectively in quantitative yields.

Process for production of alkanesulfonic acid

The present invention relates to a process for the production of alkanesulfonic acid. More particularly, the present invention relates to a process for the production of alkanesulfonic acid from alkyl mercaptan effluents generated in chemical industries. The process of the invention comprises the oxidation of the entire alkyl mercaptan generated as an effluent in the chemical industries to serve two concomitant purposes: (1) complete removal of obnoxious odour, and (2) value addition by the production of alkanesulfonic acids selectively in quantitative yields.

A new method for the synthesis of ranitidine.

An improved synthesis of the antiulcer drug Ranitidine from an oxazolidine derivative is reported.