118288-08-7

Usage

Uses

Used in Pharmaceutical Industry:
Lafutidine is used as an antiulcerative agent for its ability to inhibit gastric acid secretion and provide gastroprotective activity, making it effective in the treatment of gastritis, reflux esophagitis, and peptic ulcers.
Used in Primary Care Practice:
Lafutidine is used as an empiric treatment for patients with dyspepsia, offering superior efficacy in managing their symptoms.
Used in Research:
Lafutidine is used as a model compound to investigate the binding mechanism between antiulcer drugs and human serum albumin (HSA), contributing to the understanding of drug interactions and development of new therapeutic strategies.
Used in Treatment of NSAID-induced Ulcer:
Lafutidine is used as a treatment for nonsteroidal anti-inflammatory drug-induced ulcer in patients who are refractory to existing antiulcer agents, due to its potent H2 antagonist action and gastroprotective properties.
Brand Names:
Lafutidine is available under the brand names Stogar and Protecadin.

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)

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

• 110-89-4 piperidine 
• 118287-95-9 N-[(Z)-4-(4-Formyl-pyridin-2-yloxy)-but-2-enyl]-2-(furan-2-ylmethanesulfinyl)-acetamide 
• 118289-18-2 2-Bromo-4-[1,3]dioxolan-2-yl-pyridine 
• 118289-23-9 N-[(Z)-4-(4-[1,3]Dioxolan-2-yl-pyridin-2-yloxy)-but-2-enyl]-2-(furan-2-ylmethanesulfinyl)-acetamide 
• 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 
• 118289-21-7 2-[(Z)-4-(4-[1,3]Dioxolan-2-yl-pyridin-2-yloxy)-but-2-enyl]-isoindole-1,3-dione 
• 118289-19-3 2-[4-(2-tetrahydropyranyloxy)-(Z)-2-buten-1-yloxy]-4-(1,3-dioxolan-2-yl)-pyridine 
• 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 

Relevant academic research and scientific papers

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.

A novel histamine 2(H2) receptor antagonist with gastroprotective activity. II. Synthesis and pharmacological evaluation of 2-furfuryl-thio and 2-furfurylsulfinyl acetamide derivatives with heteroaromatic rings

We recently found that N-[3-[3- (piperidinomethyl)phenoxy]propyl]acetamide derivatives with a thioether function showed gastric anti-secretory and gastroprotective activities and that the thioether function (particularly furfurylthio or furfurylsulfinyl) was essential for gastroprotection. In the present study, a series of 2- furfurylthio and 2-furfurylsulfinyl acetamide derivatives were synthesized and evaluated for histamine H2 receptor antagonistic activity, gastric anti- secretory activity and gastroprotective action. Based on the structure of N- [3-[3-(piperidinomethyl)phenoxy]propyl]acetamide, we designed compounds, in which the 3-(piperidinomethyl)phenoxy part is substituted with many types of heteroaromatic ring attached to the tertiary amine and the propyl group is replaced with other carbon linkages. Structure-activity relationships are discussed. 2-Furfurylsulfinyl-N-[4-[4-(piperidinomethyl)-2-pyridyloxy]-(Z)- 2-butenyl]acetamide was the most potent among the tested compounds and was given the code designation FRG-8813.

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.

Preparation method and application of lafutidine and intermediate thereof

The invention relates to a preparation method and application of lafutidine and an intermediate thereof. The preparation method of the lafutidine intermediate comprises the following steps: the formula is as shown in the specification, wherein a compound shown as a formula (I) reacts in the presence of an alcohol amine type organic base and at least one type of other alkaline compound, so as to obtain the lafutidine intermediate shown as a formula (II). The preparation method of the lafutidine intermediate, disclosed by the invention, is safe and environmentally friendly, and avoids hidden dangers of safety production, caused by the fact that hydrazine hydrate, methylamine, ethanediamine, hydroxylamine hydrochloride and the like are used; the obtained lafutidine intermediate can be directly subjected to a condensation reaction to obtain the lafutidine, without the need of being further purified; the product is stable in quality and high in purity and does not contain a dihydrolafutidine impurity and the content of total impurities is lower than 0.15%; and the complicated purification is avoided and the whole process is high in yield and low in cost.

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.