WO1996034011A1 - Procedes de purification - Google Patents

Procedes de purification Download PDF

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Publication number
WO1996034011A1
WO1996034011A1 PCT/JP1996/001141 JP9601141W WO9634011A1 WO 1996034011 A1 WO1996034011 A1 WO 1996034011A1 JP 9601141 W JP9601141 W JP 9601141W WO 9634011 A1 WO9634011 A1 WO 9634011A1
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WO
WIPO (PCT)
Prior art keywords
crude
water
mixture
added
purity
Prior art date
Application number
PCT/JP1996/001141
Other languages
English (en)
Japanese (ja)
Inventor
Kazuya Nishimura
Michinori Ozawa
Akira Kagemoto
Original Assignee
Dainippon Pharmaceutical Co., Ltd.
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 Dainippon Pharmaceutical Co., Ltd. filed Critical Dainippon Pharmaceutical Co., Ltd.
Priority to AU55144/96A priority Critical patent/AU5514496A/en
Publication of WO1996034011A1 publication Critical patent/WO1996034011A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0215—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu

Definitions

  • the present invention is useful as a cardiovascular disease treating agent (2S, 3aS, 7a S) - 1 - (N 2 - Nikochino I le one L over Li Giroux 7 - D - glutamicum Le) O click evening arsenide
  • the present invention relates to an industrially advantageous purification method by crystallization and recrystallization of draw 1 H—indole 2 —carboxylic acid (hereinafter sometimes referred to as “DU—17777”).
  • DU-17777 is a compound represented by the following formula.
  • US Pat. No. 4,826,814 JP-B 5-37998 discloses that this compound is a potent angiotensin. It is disclosed that it exhibits a converting enzyme inhibitory effect and a strong and sustained antihypertensive effect.
  • Example 15 of the above-mentioned U.S. Patent three types of production examples of DU-17777 are described.
  • DU-17777 is a reversed-phase column chromatograph. Purified by a combination of fy and lyophilization and is obtained in amorphous form. That is, the reaction solution containing DU-177 7 was appropriately treated according to the reaction conditions, and then the mobile phase was changed to acetonitrile / CHP20P (0% ⁇ 60% gradient of water mixed solvent) (High-porous polystyrene resin: Applied to column chromatography of 75 to 150 ⁇ .
  • the present invention relates to a crude (2S, 3aS, 7aS)-1-(N 2 nicotinol-1 L-lysyl-1-D-daltamyl) emissions de one Lou 2 - a force carboxylic acid menu evening with Bruno Lumpur characterized the crystallization child (2S, 3aS, 7aS) - 1 one (N 2 - nicotinonitrile I le - L - lysyl - ⁇ one D- guru evening mil) O click evening purification method arsenide mud one 1 H- Lee emissions Doll one 2 _ carbonitrile phosphate and, (2) (2S, 3aS.7aS ) - 1 - (N 2 - Nicotinoy Joichi L—Rigiru 7'—D—Glutami 1H—Indone 2—Crystalline ruboric acid in water, ethylenic alcohol, and propylene One or more solvents selected from glycols and lower alkanols Where
  • “Crude D U— 1 7 7 7” refers to amorphous D U with a purity of about 85% or more.
  • the “crude crystal of DU-1777” means DU-17777 purified by crystallizing crude DU-1777 using methanol.
  • the term “lower alkanol” refers to those having 1 to 3 carbon atoms, for example, methanol, ethanol, and isopropyl alcohol, and particularly preferred is methanol.
  • "Crude DU" — 1 7 7 7 ” is acquired as follows, for example.
  • Reference Example 1 (1) to (4) or Reference Example 2 which is a method based on the method described in Example 15 of U.S. Pat. No. 4,826,814 (Japanese Patent Publication No. 5-37998). It was obtained according to the method described in (1) ⁇ (5), (2S, 3aS, 7aS - 1 one (N 2 - Nikochino Iru N 6 - Application Benefits Furuoroasechiru one L- Li di le ten 1 Echiru 7 "- D —Glutamyl) o-Hydro-1 H-indole-12 —Carboxylic acid or (2S, 3aS, 7aS) — 1- (N 6 —tert-butynecarbonyl—N 2 — Nicotinol-L—Risil ——— D—Glugyl mil 1-octahydro-1-H—indole-1—Carbonic acid is prepared in a conventional manner, for example, Reference Example 1 (5) or Reference Example 2 below
  • Crude DU-17777 is usually obtained as a syrup-like substance, and about 6.5 to about 8 times (weight ratio) of methanol is added to the crude DU-177-77. After heating to about 60 ° C to dissolve, gradually cool it while stirring, and cool to about 3 ° C if necessary. “D U-177 7 7 coarse crystals” precipitate out and are collected by filtration. The purity of the crude crystals of D U-17777 varies slightly from lot to lot, but is usually about 97.0 to about 99.0%.
  • the crude crystal is dissolved by heating in one or more solvents selected from water, ethylene glycol and propylene glycol. .
  • the amount of the solvent is usually about 0.8 to about 2.0 times the weight of the crude crystal (weight ratio), and the heating temperature is usually about 45 ° C to about 65 ° C. C is appropriate.
  • about 7 to about 11 times (weight ratio) of low-grade AlNol is added to the crude crystal, and the mixture is again heated to about 45 ° C to about 65 ° C to dissolve. Allow to cool. High purity DU-177 7 7 crystals precipitate out and are collected by filtration.
  • the optimum combination of the recrystallization solvent is a combination of water and methanol (volume ratio 1: about 8 to 10). In this case, DU-with a purity of about 99.5% or more is used. 1 7 7 7 is obtained. Even if the amount of 1Z5 to 1Z10 in the medium is replaced with acetonitrile, acetate or tetrahydrofuran during recrystallization, high-purity DU-17 7 7 can be obtained. If DU1777 having a purity of less than 99.5% is obtained, one or more solvents selected from water, ethylene glycol and propylene glycol, and a lower alcohol may be used again. It is desirable to carry out the recrystallization operation from a mixed solvent of toluene.
  • DU-17777 Due to the nature of the molecule, DU-17777 easily retains water of crystallization or crystallization solvent, and is incorporated into the molecule in any recrystallization solvent and dried. Therefore, removal is relatively difficult. In the case of pharmaceuticals, it is desirable to limit the content of methanol to less than 0.1% from the viewpoint of safety, so replace crystalline methanol with pharmaceutically acceptable ethanol. Is preferred.
  • the DU-177 7 crystal is heated and dissolved in about 0.8 to about 2.0 times (by weight) deionized water, and then DU-177 7 Add about 9 to about 11 times (weight ratio) of ethanol, and heat and dissolve again, then allow to cool. The precipitated crystals are collected by filtration and blow-dried at about 40 ° C to about 90 ° C to obtain DU-1777, which retains the crystal ethanol, which can be directly used as pharmaceuticals. It is applicable.
  • Removal of the crystallization solvent is carried out by dissolving purified DU-177 7 in deionized water, concentrating under reduced pressure if necessary, and then freeze-drying or spray-drying, whereby it can be applied as a pharmaceutical.
  • DU-1 7 7 7 can be obtained.
  • HPLC high-performance liquid chromatography
  • N 2 Benziloquinone 2
  • N 6 Trifluoroacetyl-L-Li-D-D-Duar
  • 82.2 g of ethyl ethyl phthalate was added to 820 mL of medium and add at 40-50 ° C It was dissolved by heating. Under ice-cooling, 8.2 g of 5% palladium-carbon was added, and the mixture was catalytically reduced at 25 ° C for 1 hour in a stream of hydrogen. After the reaction mixture was filtered, the filtrate was concentrated under reduced pressure to obtain 59.8 g of N 6 -trifluoroacetyl-L-lysyl-D-glucaminate.
  • the solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, and washed with a 10% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and a saturated saline solution in this order. , and dried over anhydrous sulfate Na Application Benefits um solvent was distilled off under reduced pressure (2S, 3aS.7aS) -.
  • Example 2 To the crude DU-177 7 obtained in Reference Example 1, 100 ml of evening ethanol was added and dissolved by heating at 60 ° C. This solution was allowed to cool slowly with stirring, and then further cooled with ice. The precipitated crystals were collected by filtration and washed with 10 ml of ethanol to obtain 7.5 g of DU-1777 crude crystals. The purity determined by HPLC was 98.6%.
  • Example 2 To the crude DU-177 7 obtained in Reference Example 1, 100 ml of evening ethanol was added and dissolved by heating at 60 ° C. This solution was allowed to cool slowly with stirring, and then further cooled with ice. The precipitated crystals were collected by filtration and washed with 10 ml of ethanol to obtain 7.5 g of DU-1777 crude crystals. The purity determined by HPLC was 98.6%. Example 2
  • the purification method of the present invention is an industrially extremely advantageous method because it provides high-purity DU-1777 applicable as a pharmaceutical product by a simple operation.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un procédé de purification de (2S, 3aS, 7aS)-1-(N2-nicotinoyle-L-lysyle-η-D-glutamyle)octahydro-1H-indole-2-acide carboxylique brut (DU-1777) par cristallisation à partir de méthanol; elle concerne aussi un procédé de purification de cristaux de DU-1777 brut par recristallisation à partir d'un mélange solvant comprenant un alkanol faible et au moins un solvant choisi entre l'eau, l'éhtylèneglucol et le propylèneglucol. Ces procédés présentent des avantages du point de vue industriel dans la mesure où ils permettent d'obtenir par des opérations simples du DU-1777 de grande pureté utilisable en tant que médicament.
PCT/JP1996/001141 1995-04-27 1996-04-25 Procedes de purification WO1996034011A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU55144/96A AU5514496A (en) 1995-04-27 1996-04-25 Purifying methods

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP7/128958 1995-04-27
JP12895895 1995-04-27

Publications (1)

Publication Number Publication Date
WO1996034011A1 true WO1996034011A1 (fr) 1996-10-31

Family

ID=14997625

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1996/001141 WO1996034011A1 (fr) 1995-04-27 1996-04-25 Procedes de purification

Country Status (2)

Country Link
AU (1) AU5514496A (fr)
WO (1) WO1996034011A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007031328A (ja) * 2005-07-26 2007-02-08 Tokuyama Corp Ｌ−カルノシンの製造方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63295597A (ja) * 1986-05-09 1988-12-01 Dainippon Pharmaceut Co Ltd トリペプタイド誘導体及びそれを有効成分とする心血管系疾患治療剤

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63295597A (ja) * 1986-05-09 1988-12-01 Dainippon Pharmaceut Co Ltd トリペプタイド誘導体及びそれを有効成分とする心血管系疾患治療剤

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEM. PHARM. BULL., 1990, Vol. 38, No. 1, SAWAYAMA T., "Angiotensin-Converting Enzyme Inhibitors: Synthesis and Biological Activity of N-Substituted Tripeptide Inhibitors", pages 110-115. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007031328A (ja) * 2005-07-26 2007-02-08 Tokuyama Corp Ｌ−カルノシンの製造方法
JP4540568B2 (ja) * 2005-07-26 2010-09-08 株式会社トクヤマ Ｌ−カルノシンの製造方法

Also Published As

Publication number Publication date
AU5514496A (en) 1996-11-18

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