5-Chloro-1-[1-[3-(2-oxo-1,3-dihydrobenzimidazol-1-yl)propyl]-4-piperidinyl]-1,3-dihydrobenzene Preparation method of imidazole-2-one maleate_Kain Industrial Additive

Background and overview^[1][2]

5-Chloro-1-[1-[3-(2-oxo-1,3-dihydrobenzimidazol-1-yl)propyl]-4-piperidinyl]-1,3- Dihydrobenzimidazole-2-one maleate is domperidone maleate. Domperidone maleate is a peripheral dopamine receptor blocker that directly acts on the gastrointestinal wall. It can increase the tension of the lower esophageal sphincter, prevent gastro-esophageal reflux, enhance gastric motility, promote gastric emptying, and coordinate the stomach and duodenum. Exercise can inhibit nausea and vomiting, and can effectively prevent bile reflux without affecting gastric juice secretion.

Preparation^[1]

Method 1: Using o-phenylenediamine as raw material, it first reacts with phosgene for cyclization to generate 2(3H) benzimidazolone, and then reacts the obtained product with isopropylene acetate to generate 1-(methylvinyl)- 1. 3-Dihydro-2H-benzimidazole-2-one, and then react with 1-bromo-3-chloropropane to generate 1-(methyl, vinyl)-2H-benzimidazole-2-one, and further Hydrolysis produces 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, which reacts with 5-chloro-1,3-dihydro-1-(4-piperidyl) -2H-benzimidazole-2-one reacts to form domperidone, and finally reacts with maleic acid to form domperidone maleate;

Method 2: Using 1-benzyl-4-amino-piperidine as raw material, first react with 2, 5-dichloronitrobenzene to generate benzyl aminopiperidine derivatives. Hydrogenation and reduction in the presence of Raney nickel generates the corresponding compound, cyclization with urea generates benzimidazole derivatives, and debenzenization in the presence of carbon palladium generates 5-chloro-1, 3-dihydro-1- (4-piperidinyl)-2H-benzimidazol-2-one reacts with 1-(3-chloropropane)-1, 3-dihydro-2H-benzimidazol-2-one to produce domperidone, methanol As a solvent, it reacts with maleic acid to form domperidone maleate.

Preparations^[2]

Preparation process

Pass domperidone maleate and all excipients through a 100-mesh sieve separately and set aside; weigh the prescribed amount of microcrystalline cellulose, starch, and sodium carboxymethyl starch, pass them through an 80-mesh sieve, and mix with the main drug. The pure aqueous solution made by adding 38 ml of pure water to ketone K3 0 is a soft material made of adhesive. Granulate through a 16-mesh sieve, dry at 65°C for 1 hour, and make 16-mesh granules. Weigh the prescribed amount of silica and magnesium stearate. Mix together and press into tablets to obtain.

Pharmacological effects^[3]

This product is a peripheral dopamine receptor antagonist, which can promote the peristalsis and tension of the upper gastrointestinal tract to return to normal, promote gastric emptying, enhance the movement of the gastric antrum and duodenum, coordinate the contraction of the pylorus, and also enhance the Peristalsis of the esophagus and tone of the lower esophageal sphincter. Due to its poor penetration into the blood-brain barrier and almost no antagonistic effect on dopamine receptors in the brain, mental and central nervous system side effects can be ruled out.

Pharmacokinetics^[3]

It is rapidly absorbed after oral administration, and the plasma concentration reaches its peak in 15 to 30 minutes. In addition to the central nervous system, it is widely distributed in other parts of the body. Oral bioavailability is low due to “first-pass effect” hepatic metabolism and intestinal wall metabolism. The T1/2β of this product is 7 hours, about 30% is excreted in urine 24 hours after oral administration, and about 60% is excreted in feces within 4 days.

Clinical applications and indications^[3]

5-Chloro-1-[1-[3-(2-oxo-1,3-dihydrobenzimidazol-1-yl)propyl]-4-piperidinyl]-1,3- Dihydrobenzimidazole-2-one maleate is used to treat digestive dysfunction caused by the following diseases or drugs (nausea, vomiting, loss of appetite, abdominal distension, upper abdominal discomfort, abdominal pain, stomach burning, belching, etc.) 1. Adults : Chronic gastritis, gastroptosis, reflux esophagitis, gastrectomy syndrome, and the above symptoms caused by the use of anti-malignant drugs or levodopa. 2. Children: cyclic vomiting, upper respiratory tract infections, digestive dysfunction caused by the use of anti-malignant tumor drugs, etc.

Adverse reactions^[3]

Digestive system: Diarrhea, constipation, abdominal pain, and abdominal pressure are occasionally seen; thirst, chest pain, nausea, vomiting, bloating, and transient intestinal spasm are rarely seen. This product can affect the pituitary gland located outside the blood-brain barrier and reversibly increase the level of prolactin in the blood, thereby causing galactorrhea and gynecomastia. Allergic reactions such as rash and urticaria may occasionally occur. When the blood-brain barrier is immature or impaired (in young children), unlike adults, extrapyramidal symptoms such as nervous system may occur, which may disappear after stopping the drug. Shock: It can cause shock and allergic symptoms (rash, skin redness, difficulty breathing, swollen face, swollen lips, etc.). You should pay attention to observation. When these symptoms occur, you should stop taking the drug immediately and take appropriate measures.

Drug interactions^[3]

When combined with phenothiazines, butyrophenones, and rauwolfia alkaloid preparations, endocrine dysfunction or extrapyramidal symptoms may easily occur, so use with caution. Use with caution in patients taking digitalis. Concomitant use with anticholinergic drugs may inhibit the efficacy of this product in treating dyspepsia. Theoretically, this product has a gastric motility effect, which may affect the absorption of drugs taken at the same time, especially oral preparations such as sustained-release preparations or enteric-coated preparations. However, coadministration of this product to patients who are stable on digoxin or acetaminophen has no effect on the plasma concentrations of these drugs. The product does not increase the effects of neurosedatives. The drug can inhibit the peripheral effects of dopaminergic agonists (indigestion, nausea and vomiting) without affecting the central nervous system.�. This product is mainly metabolized by CYP3A4. According to in vitro experiments, the blood concentration of this product increases when combined with CYP3A4 inhibitors. CYP3A4 inhibitors include: imidazole antifungals, macrolide antibiotics, HIV proteolytic enzyme inhibitors and nefazodone.

Notes^[3]

This product is mainly metabolized in the liver, so patients with liver damage should be careful when taking this product. Patients with renal insufficiency or urinary retention should be careful when taking this product. In patients with severe renal insufficiency (serum creatinine >6 mg/100ml), the elimination half-life of this product increases from 7.4 hours to 20.8 hours, but its plasma concentration is lower than that of healthy volunteers. Because very little of the drug is excreted unchanged in the urine, patients with renal insufficiency may not require dose adjustment after a single dose. However, when repeated administration is required, the frequency of administration should be reduced to 1 to 2 times per day according to the severity of renal function impairment, and the dosage should be reduced at the same time. Patients who require extended treatment should undergo regular examinations.

Main reference materials

[1] [China invention, China invention authorization] CN200610038526.4 Synthesis method of domperidone maleate

[2] [China invention, China invention authorization] CN201210574126.0 Domperidone maleate tablets and its preparation process

[3] Domperidone Maleate Tablets Instructions