118288-08-7

Basic information

• Product Name: Lafutidine
• Synonyms: n-(4-(4-piperidinylmethyl)pyridyl-2-oxy)butenyl-2-(furfurylsulfinyl)acetamide;LAFUTIDINE;(+-)-2-(furfurylsulfinyl)-n-(4-(4-(piperidinomethyl)-2-pyridyl)oxy-(z)-2-but;(z)-inyl)oxy)-2-butenyl);acetamide,2-((2-furanylmethyl)sulfinyl)-n-(4-((4-(1-piperidinylmethyl)-2-pyrid;enyl)acetamide;frg-8813;LAFUTIDINE(SUBJECTTOPATENTFREE)
• CAS NO: 118288-08-7
• Molecular Formula: C₂₂H₂₉N₃O₄S
• Molecular Weight: 431.55
• EINECS: 1312995-182-4
• Product Categories: Active Pharmaceutical Ingredients;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Sulfur & Selenium Compounds;Other APIs
• Mol File: 118288-08-7.mol
• Article Data: 5

Chemical Properties

• Melting Point: 92.7-94.9°
• Boiling Point: 704.2 °C at 760 mmHg
• Flash Point: 379.7 °C
• Appearance: Yellowish white crystalline powder
• Density: 1.252 g/cm³
• Vapor Pressure: 1.12E-19mmHg at 25°C
• Refractive Index: 1.598
• Storage Temp.: Sealed in dry,Store in freezer, under -20°C
• PKA: 13.13±0.46(Predicted)
• Water Solubility: Insoluble in water
• CAS DataBase Reference: Lafutidine(CAS DataBase Reference)
• NIST Chemistry Reference: Lafutidine(118288-08-7)
• EPA Substance Registry System: Lafutidine(118288-08-7)

Safety Data

• Safety Statements: 24/25
• Hazardous Substances Data: 118288-08-7(Hazardous Substances Data)

Usage

Description

Different sources of media describe the Description of 118288-08-7 differently. You can refer to the following data:
1. Lafutidine is a second generation of H2-receptor antagonist. H2-receptor antagonist can strongly inhibit gastric acid secretion compared with conventional drugs such as antacids. Unlike conventional H2-receptor antagonist, lafutidine inhibits gastric acid secretion during daytime as well as nighttime in clinical studies in humans. Lafutidine also has gastroprotective activity independent of its acid antisecretory efficacy, preventing noxious agent-induced gastric mucosal injury and accelerating the repair process following gastric mucosal damage. It also protects experimentally induced reflux esophagitis, indomethacin-induced intestinal, and dextran sulfate sodium-induced colonic inflammation. Lafutidine is used for gastric and duodenal ulcers. It is also confirmed that lafutidine can be used as an empiric treatment and superior efficacy for primary care practice patients with dyspepsia.
2. Lafutidine was launched in Japan for the treatment of gastritis, reflux oesophagitis and peptic ulcers. It can be prepared in eight steps from 4-(2-tetrahydropyranyloxy)-2(Z)-butenl- ol. Lafutidine is a potent and longer-acting H2 antagonist compared to other marketed compounds of its class such as cimetidine and famotidine. In contrast to other commercially available H2 antagonists, lafutidine also exerts a gastroprotective action probably via capsaicin-sensitive afferent nerves. It was clinically effective in the treatment of nonsteroidal antiinflammatory drug-induced ulcer in patients refractory to existing antiulcer agents.
3. Lafutidine is a histamine H2 receptor antagonist with gastroprotective activity. It inhibits histamine-induced cAMP production in CHO cells expressing human histamine H2 receptors when used at a concentration of 10 nM. Intragastric administration of lafutidine (3, 10, and 30 mg/kg) reduces hemorrhagic esophageal lesion size and gastric acid secretion in a rat model of pyloric ligation-induced reflux esophagitis. It prevents 5-fluorouracil-induced intestinal mucositis, diarrhea, and body weight loss in wild-type, but not Trpv1-/- or sensory deafferented, mice when administered at doses ranging from 3 to 30 mg/kg. Lafutidine (10 mg/kg) also reduces indomethacin-induced antral ulcer size in wild-type, but not chemically-deafferented, rats.

References

[1] Tomohiko Shimatani, Masaki Inoue, Tomoko Kuroiwa, Jing Xu, Masuo Nakamura, Susumu Tazuma, Kazuro Ikawa, Norifumi Morikawa (2006) Lafutidine, a Newly Developed Antiulcer Drug, Elevates Postprandial Intragastric pH and Increases Plasma Calcitonin Gene-Related Peptide and Somatostatin Concentrations in Humans: Comparisons with Famotidine, Digestive Diseases and Sciences, 51, 114-120 [2] Bhupesh Dewan, Nisha Philipose (2011) Lafutidine 10 mg versus Rabeprazole 20 mg in the Treatment of Patients with Heartburn-Dominant Uninvestigated Dyspepsia: A Randomized, Multicentric Trial, Gastroenterology Research and Practice, 2011, Article ID 640685 [3] https://www.drugs.com

Originator

Fujirebio (Japan)

Uses

Different sources of media describe the Uses of 118288-08-7 differently. You can refer to the following data:
1. (Z)-2-((Furan-2-ylmethyl)sulfinyl)-n-(4-((3-(piperidin-1-ylmethyl)pyridin-2-yl)oxy)but-2-en-1-yl)acetamide is a Histaminic H2 receptor antagonists in ulcer disease. Also, it is a model compound used to investigate the binding mechanism between antiulcer drugs and human serum albumin (HSA).
2. Second generation histamine H2-receptor antagonist. Antiulcerative
3. Lafutidine, a newly developed histamine H(2)-receptor antagonist, inhibits gastric acid secretion

Brand name

Stogar, Protecadin

InChI:InChI=1/C22H29N3O4S/c26-21(18-30(27)17-20-7-6-14-28-20)23-9-2-5-13-29-22-15-19(8-10-24-22)16-25-11-3-1-4-12-25/h2,5-8,10,14-15H,1,3-4,9,11-13,16-18H2,(H,23,26)/b5-2-

Synthetic route

(2Z)-4-({4-[(piperidin-1-yl)methyl]pyridin-2-yl}oxy)but-2-en-1-amine + p-nitrophenyl 2-(furfurylsulfinyl)acetate → lafutidine (118288-08-7)

Conditions	Yield
In dichloromethane at 25 - 30℃;	94.6%
In tetrahydrofuran at 5 - 20℃; for 19h; Large scale;	91.3%
In Isopropyl acetate at 35 - 40℃; for 5h; Solvent;	87%
In ethyl acetate at 20℃;	60%

piperidine (110-89-4) + N-[(Z)-4-(4-Formyl-pyridin-2-yloxy)-but-2-enyl]-2-(furan-2-ylmethanesulfinyl)-acetamide (118287-95-9) → lafutidine (118288-08-7)

Conditions	Yield
With sodium tetrahydroborate 1.) EtOH, 3 h, 2.) EtOH, 16 h; Yield given. Multistep reaction;

2-Bromo-4-[1,3]dioxolan-2-yl-pyridine → lafutidine (118288-08-7)

Conditions

Yield

Multi-step reaction with 8 steps 1: 87 percent / NaOH, K2CO3, n-Bu4NHSO4 / toluene / 18 h / Ambient temperature 2: 90 percent / pyridinium p-toluenesulfonate, ethanol / 18 h / 55 °C 3: SOCl2, Et3N / CH2Cl2 / 1 h / 0 °C 4: n-Bu4NHSO4 / acetonitrile / 18 h / Heating 5: 78 percent / NH2NH2*H2O / methanol / 10 h / Heating 6: 91 percent / tetrahydrofuran / 18 h / Ambient temperature 7: 52 percent / p-TsOH, H2O / acetone / 18 h / Heating 8: 2.) NaBH4 / 1.) EtOH, 3 h, 2.) EtOH, 16 h View Scheme

(Z)-4-(4-[1,3]Dioxolan-2-yl-pyridin-2-yloxy)-but-2-enylamine (118289-22-8) → lafutidine (118288-08-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: 91 percent / tetrahydrofuran / 18 h / Ambient temperature 2: 52 percent / p-TsOH, H2O / acetone / 18 h / Heating 3: 2.) NaBH4 / 1.) EtOH, 3 h, 2.) EtOH, 16 h View Scheme

4-[4-(1,3-dioxolan-2-yl)-2-pyridyloxy]-(Z)-2-buten-1-ol (118289-20-6) → lafutidine (118288-08-7)

Conditions	Yield
Multi-step reaction with 6 steps 1: SOCl2, Et3N / CH2Cl2 / 1 h / 0 °C 2: n-Bu4NHSO4 / acetonitrile / 18 h / Heating 3: 78 percent / NH2NH2*H2O / methanol / 10 h / Heating 4: 91 percent / tetrahydrofuran / 18 h / Ambient temperature 5: 52 percent / p-TsOH, H2O / acetone / 18 h / Heating 6: 2.) NaBH4 / 1.) EtOH, 3 h, 2.) EtOH, 16 h View Scheme

2-((Z)-4-Chloro-but-2-enyloxy)-4-[1,3]dioxolan-2-yl-pyridine → lafutidine (118288-08-7)

Conditions	Yield
Multi-step reaction with 5 steps 1: n-Bu4NHSO4 / acetonitrile / 18 h / Heating 2: 78 percent / NH2NH2*H2O / methanol / 10 h / Heating 3: 91 percent / tetrahydrofuran / 18 h / Ambient temperature 4: 52 percent / p-TsOH, H2O / acetone / 18 h / Heating 5: 2.) NaBH4 / 1.) EtOH, 3 h, 2.) EtOH, 16 h View Scheme

2-[4-(2-tetrahydropyranyloxy)-(Z)-2-buten-1-yloxy]-4-(1,3-dioxolan-2-yl)-pyridine (118289-19-3) → lafutidine (118288-08-7)

Conditions

Yield

Multi-step reaction with 7 steps 1: 90 percent / pyridinium p-toluenesulfonate, ethanol / 18 h / 55 °C 2: SOCl2, Et3N / CH2Cl2 / 1 h / 0 °C 3: n-Bu4NHSO4 / acetonitrile / 18 h / Heating 4: 78 percent / NH2NH2*H2O / methanol / 10 h / Heating 5: 91 percent / tetrahydrofuran / 18 h / Ambient temperature 6: 52 percent / p-TsOH, H2O / acetone / 18 h / Heating 7: 2.) NaBH4 / 1.) EtOH, 3 h, 2.) EtOH, 16 h View Scheme

2-[(Z)-4-(4-[1,3]Dioxolan-2-yl-pyridin-2-yloxy)-but-2-enyl]-isoindole-1,3-dione (118289-21-7) → lafutidine (118288-08-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: 78 percent / NH2NH2*H2O / methanol / 10 h / Heating 2: 91 percent / tetrahydrofuran / 18 h / Ambient temperature 3: 52 percent / p-TsOH, H2O / acetone / 18 h / Heating 4: 2.) NaBH4 / 1.) EtOH, 3 h, 2.) EtOH, 16 h View Scheme

N-[(Z)-4-(4-[1,3]Dioxolan-2-yl-pyridin-2-yloxy)-but-2-enyl]-2-(furan-2-ylmethanesulfinyl)-acetamide (118289-23-9) → lafutidine (118288-08-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 52 percent / p-TsOH, H2O / acetone / 18 h / Heating 2: 2.) NaBH4 / 1.) EtOH, 3 h, 2.) EtOH, 16 h View Scheme

(Z)-4-(Piperidin-1-ylmethyl)-2-((4-((tetrahydro-2H-pyran2-yl)oxy)but-2-en-1-yl)oxy)pyridine (146270-02-2) → lafutidine (118288-08-7)

Conditions

Yield

Multi-step reaction with 5 steps 1: hydrogenchloride / ethyl acetate; water / 2 h / 25 °C / Large scale 2: potassium carbonate; thionyl chloride / dichloromethane / 2 h / 0 - 25 °C / Large scale 3: tetra(n-butyl)ammonium hydrogensulfate / acetonitrile / 18 h / Reflux; Large scale 4: hydrazine hydrate; 1-hexene / methanol / 4 h / Reflux; Large scale 5: tetrahydrofuran / 19 h / 5 - 20 °C / Large scale View Scheme

(Z)-4-((4-(Piperidin-1-ylmethyl)pyridin-2-yl)oxy)but-2-en-1-ol → lafutidine (118288-08-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: potassium carbonate; thionyl chloride / dichloromethane / 2 h / 0 - 25 °C / Large scale 2: tetra(n-butyl)ammonium hydrogensulfate / acetonitrile / 18 h / Reflux; Large scale 3: hydrazine hydrate; 1-hexene / methanol / 4 h / Reflux; Large scale 4: tetrahydrofuran / 19 h / 5 - 20 °C / Large scale View Scheme

C15H21ClN2O → lafutidine (118288-08-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: tetra(n-butyl)ammonium hydrogensulfate / acetonitrile / 18 h / Reflux; Large scale 2: hydrazine hydrate; 1-hexene / methanol / 4 h / Reflux; Large scale 3: tetrahydrofuran / 19 h / 5 - 20 °C / Large scale View Scheme

2-chloro-4-(1-piperidinomethyl)-pyridine → lafutidine (118288-08-7)

Conditions

Yield

Multi-step reaction with 6 steps 1: potassium carbonate; sodium hydroxide; tetra(n-butyl)ammonium hydrogensulfate / toluene / 15 h / Reflux; Large scale 2: hydrogenchloride / ethyl acetate; water / 2 h / 25 °C / Large scale 3: potassium carbonate; thionyl chloride / dichloromethane / 2 h / 0 - 25 °C / Large scale 4: tetra(n-butyl)ammonium hydrogensulfate / acetonitrile / 18 h / Reflux; Large scale 5: hydrazine hydrate; 1-hexene / methanol / 4 h / Reflux; Large scale 6: tetrahydrofuran / 19 h / 5 - 20 °C / Large scale View Scheme

Upstream product

• 123855-55-0 p-nitrophenyl 2-(furfurylsulfinyl)acetate 
• 146270-01-1 2-chloro-4-(1-piperidinomethyl)-pyridine 
• 146270-02-2 (Z)-4-(Piperidin-1-ylmethyl)-2-((4-((tetrahydro-2H-pyran2-yl)oxy)but-2-en-1-yl)oxy)pyridine 
• 118289-19-3 2-[4-(2-tetrahydropyranyloxy)-(Z)-2-buten-1-yloxy]-4-(1,3-dioxolan-2-yl)-pyridine 
• 118289-18-2 2-Bromo-4-[1,3]dioxolan-2-yl-pyridine 
• 110-89-4 piperidine 
• 118287-95-9 N-[(Z)-4-(4-Formyl-pyridin-2-yloxy)-but-2-enyl]-2-(furan-2-ylmethanesulfinyl)-acetamide 
• 118289-20-6 4-[4-(1,3-dioxolan-2-yl)-2-pyridyloxy]-(Z)-2-buten-1-ol 
• 118289-22-8 (Z)-4-(4-[1,3]Dioxolan-2-yl-pyridin-2-yloxy)-but-2-enylamine 
• 118289-23-9 N-[(Z)-4-(4-[1,3]Dioxolan-2-yl-pyridin-2-yloxy)-but-2-enyl]-2-(furan-2-ylmethanesulfinyl)-acetamide 
• 118289-21-7 2-[(Z)-4-(4-[1,3]Dioxolan-2-yl-pyridin-2-yloxy)-but-2-enyl]-isoindole-1,3-dione 

Relevant articles and documents

Increasing the Purity of Lafutidine Using a suicide Substrate

When preparing lafutidine, we found that the main impurity was dihydrolafutidine. On the basis of the chemical structure of dihydrolafutidine and the mechanism of its production, we decided to use a suicide substrate in the drug preparation to increase the purity of lafutidine. By calculating the energy barrier of the reduction reaction with a quantum-chemical method and evaluating the appropriate physicochemical properties of the terminal olefins, we chose 1-hexene as the suicide substrate to effectively control the formation of dihydrolafutidine in the synthesis of lafutidine. The experimental results showed that the content of the impurity, dihydrolafutidine, decreased from 1.5% to less than 0.05%, proving that using a suicide substrate is an effective method to reduce the formation of the relevant byproduct in drug production. In addition, this method is operationally simple and is suitable for industrial applications.

Method for manufacturing lafutidine crystal with high purity

The present invention relates to a method for manufacturing a lafutidine crystal form with high purity. The method for manufacturing a novel lafutidine crystal form of the present invention produces a desired crystal form according to temperature control after dissolution, thereby being able to be easily applied to production (scale-up) and stably manufacture the lafutidine crystal form with high purity.

Lafutidine hydroxylamine hydrochloride method of preparation

The invention relates to a novel chemical synthetic method for lafutidine, and in particular relates to a method for preparing the lafutidine from hydroxylamine hydrochloride serving as aminolysis reagent. The method comprises the following steps of: (1) reacting a compound in a formula 4 with the hydroxylamine hydrochloride and sodium hydroxide so as to obtain a compound in a formula 2; (2) carrying out condensation on the compound in the formula 2 and a compound in a formula 3 so as to obtain the lafutidine in a formula 1. The whole preparation process is as shown in the specification. When in preparation of the key intermediate the compound in the formula 2, the hydroxylamine hydrochloride is chosen for substituting other reagents for aminolysis reaction, and the prepared lafutidine product has higher purity and can reach 99.88%; compared with the condition that the aminolysis reagent is removed from the intermediate, the hydroxylamine is easier to remove; and furthermore, the hydroxylamine hydrochloride is a solid reagent, has high purity and high stability, and industrial production is more easily realized.