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WO2002048120A1 - Nouveaux cristaux de derives d'oxazepine et procede de production de ces derniers - Google Patents

Nouveaux cristaux de derives d'oxazepine et procede de production de ces derniers Download PDF

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Publication number
WO2002048120A1
WO2002048120A1 PCT/JP2000/008739 JP0008739W WO0248120A1 WO 2002048120 A1 WO2002048120 A1 WO 2002048120A1 JP 0008739 W JP0008739 W JP 0008739W WO 0248120 A1 WO0248120 A1 WO 0248120A1
Authority
WO
WIPO (PCT)
Prior art keywords
oxazepine
dihydro
dibenzo
methoxyphenethyl
pyrrolidinylmethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2000/008739
Other languages
English (en)
Japanese (ja)
Inventor
Toshihiro Matsuzawa
Takaaki Sekiyama
Masanobu Yatagai
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ajinomoto Co Inc
Original Assignee
Ajinomoto Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ajinomoto Co Inc filed Critical Ajinomoto Co Inc
Priority to AU2001217359A priority Critical patent/AU2001217359A1/en
Priority to PCT/JP2000/008739 priority patent/WO2002048120A1/fr
Publication of WO2002048120A1 publication Critical patent/WO2002048120A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the present invention has a calcium channel antagonism, and is useful for treating or preventing intestinal diseases such as gastrointestinal dysfunction, particularly irritable bowel syndrome, and 5,11-dihydrodibenzo [b, e] [ 1,4]
  • intestinal diseases such as gastrointestinal dysfunction, particularly irritable bowel syndrome
  • Method for producing oxazepine derivatives more specifically 5,11-dihydro-1-5- [1- (4-methoxyphenethyl) -12-pyrrolidinylmethyl] dibenzo [b, e] [1,4]
  • a method for purifying oxazepine for purifying oxazepine.
  • Oxazepine has a calcium channel antagonism, and is known to be useful for treating or preventing intestinal diseases such as gastrointestinal dysfunction, particularly irritable bowel syndrome (W097 / 33885).
  • An object of the present invention is to provide a method for preparing 5,11-dihydro-5- [1- (4-methoxyphenethyl) -2-pyrrolidinylmethyl] dibenzo [b, e] [1,4] oxazebine. To provide an acid salt, and to establish an industrially useful production method thereof.
  • the present inventors have conducted intensive studies to solve the above problems, and as a result, have found that 5,11-dihydrodibenzo [b, e] [1,4] oxazepine (2) and optically active 1- (4-Methoxyphenyl) piperidine, for example (S)-(+)-3
  • the solvent is added to the oily residue obtained by extracting and concentrating the reaction solution of (4-methoxyphenethyl) piperidine (3) with an organic solvent.
  • the present invention relates to 5,11-dihydro-5- [1- (4-methoxyphenyl) -12-pyrrolidinylmethyl] dibenzo [b, e] [1,4] oxazepine nitrate, particularly (R) -(+) —5,11-dihydro-5- [1- (4-methoxyphenethyl) —2-pyrrolidinylmethyl] dibenzo [b, e] [1,4] Oxazepine .
  • the present invention also provides a reaction between 5,11-dihydrodibenzo [b, e] [1,4] oxazepine (2) and an optically active 3-chloro-1- (4-methoxyphenethyl) piberidine.
  • an extraction solvent such as ethyl acetate, toluene, dichloromethane, isopropyl acetate, etc.
  • an extraction solvent such as ethyl acetate, toluene, dichloromethane, isopropyl acetate, etc.
  • wash with water, saturated saline, etc. and if necessary After drying over anhydrous sodium sulfate and concentrating, the optically active 5,11-dihydro-5- [1- (4-methoxyphenethyl) -12-pyrrolidinylmethyl] dibenzo [b, e] [1,4] oxazepine
  • a mixture of optically active 5,11-dihydro-5- [1- [2- (4-methoxyphenyl) ethyl] piridin-13-yl] dibenzo [b, e] [1,4] oxazepine Can be obtained as an oily residue.
  • a solvent such as methanol, ethanol, 2-propanol, acetonitrile, or acetone is added to the oily residue obtained above to dissolve the oily residue.
  • concentration at the time of dissolution depends on the temperature, but is preferably from 0.1 to 30 wt%, more preferably from 1 to 1 wt%, particularly preferably from 3 to 5 wt% when the reaction is carried out at 20 to 25 ° C.
  • the target nitrate is precipitated by adding nitric acid to this solution, and the temperature for adding nitric acid is preferably 20 to 60 ° C, more preferably 30 to 50 ° C, depending on the boiling point of the solvent used. And good. Further, the concentration of nitric acid to be added is preferably 0.25 to 1 normal, more preferably 0.4 to 0.6 normal. After adding the nitric acid, the desired crystals can be obtained preferably by leaving the mixture at room temperature (20 to 25 ° C.) for 6 to 24 hours. In this case, there is no problem even if stirring is performed. I can't.
  • the target crystals can be isolated from the precipitated crystals by a usual separation method, for example, filtration or shaking-off. Usually, the purity of the target compound can be increased by washing with a mixed solvent of water and water used for crystallization. Further, by drying this crystal, the desired nitrate can be obtained.
  • the researchers of the present invention firstly set the target (R)-(+)-5,11-dihydro-1-5- [1- (4-methoxyphenethyl) 12 —Pyrrolidinylmethyl] dibenzo [b, e] [1,4] oxazepine (1) was crystallized using various solvents, but no solvent was able to precipitate crystals. ⁇
  • salts for acids other than nitric acid such as acetic acid, formic acid, DL-tartaric acid, maleic acid, fumaric acid, succinic acid, adipic acid, p-toluenesulfonic acid, methanesulfonic acid, camphorsulfonic acid, and sulfuric acid. Attempted, but none of them could obtain the desired salt.
  • the obtained nitrate is suspended in an extraction solvent such as ethyl acetate, neutralized with an aqueous alkali solution such as an aqueous solution of sodium hydroxide, separated, and the organic layer is washed with saturated saline and concentrated as necessary. Then, a hydrogen chloride / ethyl acetate solution or the like is added dropwise to the solution, so that it is actually used as a medicine.
  • an extraction solvent such as ethyl acetate
  • an aqueous alkali solution such as an aqueous solution of sodium hydroxide
  • the present invention also provides a method for preparing 5,11-dihydro-5-C1- (4-methoxyphenethyl) -12-pyrrolidinylmethyl] dibenzo [b, e] [1,4] oxazepine according to the method of the present invention.
  • a pharmaceutical composition comprising a hydrochloride salt of the compound produced from nitrate and a pharmaceutically acceptable carrier or adjuvant.
  • the pharmaceutical composition of the present invention has a calcium antagonism and is effective in treating gastrointestinal motility disorders, particularly irritable bowel syndrome. Useful for therapy or prevention.
  • pharmaceutically acceptable carriers or adjuvants include those usually used for preventing or treating gastrointestinal motility dysfunction. Such carriers or adjuvants will be apparent to those skilled in the art. It is.
  • the pharmaceutical composition of the present invention can be prepared by a conventional method, such as injection, tablet, granule, fine granule, powder, capsule, cream, suppository, etc., by oral administration, intravenous administration, transdermal It can be administered or instilled. Dosage will vary depending on the condition, age, and manner of administration of the subject.
  • 13C thigh (CDC13): 24.3, 30.5, 32.6, 53.5, 55.2, 57.6, 59.6, 60.8, 70.3, 113.8, 119.6, 120.9, 124.1, 124.5, 124.9, 125.3, 128.7, 128.8, 129.5, 132.4, 133.2, 135.6, 148.4, 151.1, 157.9.
  • Oxazepine reacted with the optically active 3-chloro-1- (4-methoxyphenethyl) piperidine to obtain the desired optically active 5,11-dihydroamine 5- [1- (4-Methoxyphenyl) -1-pyrrolidinylmethyl] dibenzo [b, e] [1,4] oxazepine and optically active 5,11-dihydro-5- [1 — C2- (4-Methoxyphenyl) ethyl] piperidin-1-3-yl] dipenza [b, e] [1,4] Oxazepine mixture from desired optically active 5,11-dihydro-5- [1- (4-Methoxyphenethyl) -1-pyrrolidinylmethyl] dibenzo [b, e] [1, 4] Oxazepine can be easily prepared without using an industrially complicated purification method such as column chromatography.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé qui consiste à dissoudre, dans un solvant, un mélange de 5,11-dihydro-5-[1-(4-méthoxyphénylméthyl)- 2-pyrrolidinylméthyl]dibenzo[b,e][1,4]oxazépine optiquement active et de 5,11-dihydro-5-[1-[2-(4-méthoxyphényl)-éthyl]pipéridin-3-yl]dibenzo[b,e]oxazépine optiquement active; à ajouter de l'acide nitrique à la solution obtenue pour précipiter les cristaux; puis à séparer ces cristaux du système résultant.
PCT/JP2000/008739 2000-12-11 2000-12-11 Nouveaux cristaux de derives d'oxazepine et procede de production de ces derniers Ceased WO2002048120A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2001217359A AU2001217359A1 (en) 2000-12-11 2000-12-11 Novel crystals of oxazepine derivatives and process for the production thereof
PCT/JP2000/008739 WO2002048120A1 (fr) 2000-12-11 2000-12-11 Nouveaux cristaux de derives d'oxazepine et procede de production de ces derniers

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP2000/008739 WO2002048120A1 (fr) 2000-12-11 2000-12-11 Nouveaux cristaux de derives d'oxazepine et procede de production de ces derniers

Publications (1)

Publication Number Publication Date
WO2002048120A1 true WO2002048120A1 (fr) 2002-06-20

Family

ID=11736783

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2000/008739 Ceased WO2002048120A1 (fr) 2000-12-11 2000-12-11 Nouveaux cristaux de derives d'oxazepine et procede de production de ces derniers

Country Status (2)

Country Link
AU (1) AU2001217359A1 (fr)
WO (1) WO2002048120A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7320973B2 (en) 2001-05-30 2008-01-22 Ajinomoto Co., Inc. Dihydrodiaryloxazepine derivative and pharmaceutical composition containing the same

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997033885A1 (fr) * 1996-03-11 1997-09-18 Ajinomoto., Inc. DERIVES DE 5,11-DIHYDRODIBENZ[b,e] [1,4]OXAZEPINE, ET COMPOSITIONS MEDICAMENTEUSES LES COMPORTANT

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997033885A1 (fr) * 1996-03-11 1997-09-18 Ajinomoto., Inc. DERIVES DE 5,11-DIHYDRODIBENZ[b,e] [1,4]OXAZEPINE, ET COMPOSITIONS MEDICAMENTEUSES LES COMPORTANT

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7320973B2 (en) 2001-05-30 2008-01-22 Ajinomoto Co., Inc. Dihydrodiaryloxazepine derivative and pharmaceutical composition containing the same

Also Published As

Publication number Publication date
AU2001217359A1 (en) 2002-06-24

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