1. Dissolve 2-bromo-4-pyridine in methanol in CH2Cl2, add C4H9)4NBr and benzenesulfonyl chloride, stir, and add a solution prepared with NaOH dropwise while stirring. Maintain the temperature at approximately 25 °C and stir vigorously for 1–2 h. Separate the solutions, concentrate, and pour the residue into diethyl ether while stirring. A light brown solid, benzenesulfonic acid-(2-bromo-4-pyridine methyl) ester, precipitates.
2. Add benzenesulfonic acid-(2-bromo-4-pyridine methyl) ester and K2CO3 to a three-necked flask, add butanone, and slowly add piperidine. Reflux for 2–3 h, filter while hot, wash the filter cake with butanone, combine the butanone, wash the butanone twice with water, concentrate, and obtain a brown oily substance, 4-(2-oxotetrahydropyranyl)-cis-2-buten-1-ol. 3. Take 4-(2-oxotetrahydropyranyl)-cis-2-buten-1-ol, 2-bromo-4-(piperidinylmethyl)pyridine (VI), NaOH, K2CO3, and (C4H9)4NBr, place them in a three-necked flask, heat to 105 °C and stir for 36 h. Pour the reaction solution into twice the volume of water, separate the layers, extract the aqueous layer with toluene 2-3 times, and wash once with water to obtain 2-[4-(2-oxotetrahydropyranyl)-cis-2-buten-1-oxo]-4-(1-piperidinyl)pyridine. 4. Add 2-[4-(2-oxotetrahydropyranyl)-cis-2-buten-1-oxo]-4-(1-piperidinyl)pyridine and toluene to concentrated HCl, stir at room temperature for 12 h, let stand, separate the layers, combine the aqueous layers, wash with chloroform and ethyl acetate respectively, adjust the pH to 10-11, extract with chloroform 3 times, filter the chloroform layer under vacuum with a 1.5 cm thick silica gel layer, evaporate the filtrate to dryness to obtain 4-[4-(1-piperidinylmethyl)pyridine-2-oxo]-cis-2-buten-1-ol. 5. Add 4-[4-(1-piperidinylmethyl)pyridine-2-oxo]-cis-2-buten-1-ol to a three-necked flask, dissolve it in CH2Cl2, and cool with ice water. Add K2CO3, then add thionyl chloride dropwise. After the addition is complete, raise the temperature to room temperature and continue stirring for 4-5 h. Filter, add saturated NaHCO3 aqueous solution to the filtrate, adjust to weak alkalinity, separate the organic phase, wash the organic phase once with water, separate the layers, filter, dry the filtrate, and distill under reduced pressure to obtain the product 4-[4-(1-piperidinylmethyl)pyridine-2-oxo]-cis-2-buten-1-chloro. 6. 4-[4-(1-piperidinylmethyl)pyridine-2-oxy]-cis-2-butene-1-chloro, toluene, potassium phthalimide, (C4H9)4NBr were heated to 80 °C and stirred for 6 h. After cooling, the mixture was washed with 1 mol/L NaOH aqueous solution, washed once with water, filtered, and concentrated to obtain a yellow oily substance N-[4-[4-(1-piperidinylmethyl)pyridine-2-oxy]-cis-2-butene]phthalimide. 7. Dissolve maleate in 15% K2CO3, add 650 mL toluene and 50 mL ethanol, stir to dissolve, and separate the liquid. Add hydrazine hydrate to the organic phase, heat to reflux, the solid dissolves first, and then another solid precipitates. Reflux for 2-3 h, concentrate, and obtain a light yellow solid 4-[4-(1-piperidinylmethyl)pyridine-2-oxo]-cis-butenyl-1-amine. 8. Add 4-[4-(1-piperidinylmethyl)pyridine-2-oxo]-cis-butenyl-1-amine and ethyl acetate to a three-necked flask. Add furanylmethylsulfinylacetic acid (p-nitrophenol) ester in batches and stir for 4-5 h. Add 15% acetic acid and stir for 0.5 h. Separate the liquid and extract the organic phase with 15% acetic acid. Separate the liquid and extract the aqueous phase. Extract the aqueous layer with ethyl acetate again and separate the aqueous phase. Adjust the pH to 9-10 with potassium carbonate and extract with ethyl acetate 2-3 times. Combine the ethyl acetate layers and wash with 1 mol/L NaOH until nearly colorless. Wash once with saturated NaCl, dry, filter, evaporate to dryness, add a small amount of petroleum ether and ethanol, stir, and precipitate a white solid, lafutidine.
[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
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.
[1] Y. FUKUSHIMA. Potent and Long-Lasting Action of Lafutidine on the Human Histamine H2 Receptor[J]. Digestion, 2001, 64 1: 155-160. DOI:
10.1159/000048856[2] KENJI NAGAHAMA. Protective effect of lafutidine, a novel H2-receptor antagonist, on reflux esophagitis in rats through capsaicin-sensitive afferent neurons.[J]. Journal of pharmacological sciences, 2003, 93 1: 55-61. DOI:
10.1254/jphs.93.55[3] T SANO. Lafutidine, a histamine H2 receptor antagonist with mucosal protective properties, attenuates 5-fluorouracil-induced intestinal mucositis in mice through activation of extrinsic primary afferent neurons.[J]. Journal of Physiology and Pharmacology, 2017, 68 1: 79-90.
[4] S ONODERA. Gastroprotective mechanism of lafutidine, a novel anti-ulcer drug with histamine H2-receptor antagonistic activity.[J]. Arzneimittel-Forschung-Drug Research, 1999, 49 6: 519-526. DOI:
10.1055/s-0031-1300454
