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WO2012148148A9 - Nouveau complexe d'azide de zinc et procédé de préparation de dérivés de tétrazole l'utilisant - Google Patents

Nouveau complexe d'azide de zinc et procédé de préparation de dérivés de tétrazole l'utilisant Download PDF

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Publication number
WO2012148148A9
WO2012148148A9 PCT/KR2012/003135 KR2012003135W WO2012148148A9 WO 2012148148 A9 WO2012148148 A9 WO 2012148148A9 KR 2012003135 W KR2012003135 W KR 2012003135W WO 2012148148 A9 WO2012148148 A9 WO 2012148148A9
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WIPO (PCT)
Prior art keywords
alkyl
zinc
azide
formula
added
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PCT/KR2012/003135
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English (en)
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WO2012148148A2 (fr
WO2012148148A3 (fr
Inventor
Byeong Cheol Kim
Sei Chang Ahn
Hyun Ik Shin
In Sang Lee
Young Keun Kim
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LG Chem Ltd
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LG Life Sciences Ltd
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Publication of WO2012148148A2 publication Critical patent/WO2012148148A2/fr
Publication of WO2012148148A3 publication Critical patent/WO2012148148A3/fr
Publication of WO2012148148A9 publication Critical patent/WO2012148148A9/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
    • C07F3/06—Zinc compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings

Definitions

  • the present invention relates to a novel zinc azide complex.
  • the present invention also relates to a process for preparing 5-substituted-1H-tetrazole derivatives from nitrile derivatives by using the zinc azide complex.
  • pharmaceutically active compounds for treating hypertension or intermediates useful for preparation thereof can be prepared effectively.
  • tetrazole groups are often used as metabolism-resistant isosteric replacement for carboxylic acids in a living body. Thus, they act as an essential component in agents for treating various important diseases.
  • the compounds such as Losartan-potassium, Valsartan, Candesartan cilexetil, Irbesartan, Olmesartan medoxomil and Fimasartan of the following chemical formulas, which are widely known as angiotensin II receptor blockers (ARBs) and so used for treating hypertension and congestive heart failure, have in common a tetrazole group.
  • ARBs angiotensin II receptor blockers
  • 2006/0038994 shows that the preparation of Valsartan using diisobutyl-Al-azide resulted in a low conversion rate of about 77% and the remaining about 23% of the starting material, although the Al-azide was added two times (1.4 equivalents for the first and 0.8 equivalent for the second) and the reaction was conducted at high temperature (110 ⁇ 130°C).
  • a method of using a zinc salt (Zn salt) for example, zinc chloride (ZnCl 2 ) or zinc bromide (ZnBr 2 )
  • Zn salt for example, zinc chloride (ZnCl 2 ) or zinc bromide (ZnBr 2 )
  • sodium azide is known as a safe and effective method for preparing tetrazole derivatives (B.M. Sharpless et al., J. Org. Chem. , 2001, 66, 7945), and such methods are disclosed in International Publication No. WO 1996/037481, US Patent No. 5,502,191, etc.
  • sterically hindered nitriles such as biphenyl nitriles like Valsartan require a long reaction time at high temperature and excessive zinc salt and sodium azide in order to complete the reaction. Accordingly, the method of using zinc salt and sodium azide is insufficient to resolve the aforesaid problems.
  • the present inventors have conducted intensive research to develop a process which can remarkably improve the aforesaid problems that conventional processes have in preparing ARB series compounds.
  • the aforesaid problems are long reaction time, use of highly toxic tin metal, use of excessive azide salt, low reaction conversion rate and yield, risk of explosion due to sublimating byproduct, etc.
  • This invention has come from our efforts to develop a process that is economical, environment-friendly and suitable for large-scale commercial production by overcoming the aforesaid problems.
  • the present invention relates to a novel zinc azide complex of the following formula 3:
  • X represents NO 3 , OH, Cl, Br, I or a combination thereof
  • L represents an amine ligand that can coordinate with Zn
  • a, b and c satisfy 0 ⁇ a ⁇ 2, 0 ⁇ b ⁇ 4 and 0 ⁇ c ⁇ 2, respectively.
  • L represents a bidentate ligand selected from the following group:
  • TEDA N,N,N’,N’-tetramethylethylenediamine
  • a zinc compound for example, zinc nitrate hexahydrate, zinc chloride, zinc bromide or zinc iodide
  • an alkali metal azide for example, lithium azide, sodium azide or potassium azide
  • An amine ligand for example, N,N,N’,N’-tetramethylethylenediamine (TMEDA)
  • TEDA N,N,N’,N’-tetramethylethylenediamine
  • the zinc azide complex obtained as such is in a mixture form and is represented by formula 3. It can also be used after purification. However, there is no significant difference in the results from a use of mixture form complex and that of purified form.
  • the structure of the zinc azide complex obtained after purification is represented in Figure 1.
  • Zn(TMEDA)(N 3 ) 2 which is a zinc azide complex of formula 3 wherein a is 1, b is 2, c is 0, and L is N,N,N’,N’-tetramethylethylenediamine (TMEDA), may be referred to as the representative zinc azide complex according to the present invention.
  • [Zn(NO 3 ) 2 ⁇ 6H 2 O, NaN 3 and TMEDA] mixture or [ZnCl 2 , NaN 3 and TMEDA] mixture may be referred to as the corresponding mixture.
  • the present invention also relates to a process for preparing a substituted tetrazole derivative of formula 1.
  • This process comprises reacting the zinc azide complex of formula 3, which is prepared by the complex formation reaction, with a nitrile compound of formula 2 after isolation or in situ .
  • R represents an organic residual group
  • X, L, a, b and c are the same as defined above.
  • R represents linear or branched C 1 -C 6 -alkyl or C 3 -C 6 -cycloalkyl, each of which is optionally substituted with one or more (preferably, 1 to 4) substituents selected from:
  • phenyl pyridine, pyrimidine, imidazole, thiophene and furan, each of which is optionally substituted with one or more (preferably, 1 to 4) substituents selected from the group consisting of C 1 -C 6 -alkyl, halogen, hydroxy, nitro and C 1 -C 6 -alkoxy,
  • R represents phenyl or biphenyl of the following formula:
  • each of R1 and R2 is independently selected from the group consisting of
  • C 1 -C 6 -alkyl for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, hexyl
  • C 3 -C 6 -cycloalkyl for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl
  • R 3 represents hydrogen or methyl.
  • R 4 represents hydrogen, methyl, ethyl or cilexetil.
  • R 5 represents hydrogen, methyl, ethyl or medoxomil.
  • the starting material of formula 2 may be added to and react in situ with the zinc azide complex that is obtained by the zinc azide complex formation reaction without the filtering and drying steps.
  • the zinc azide complex is isolated and then used.
  • the reaction for preparing the formula 1 compound according to the present invention uses a single or mixture solvent selected from the group consisting of toluene; xylene; ethylbenzene; halogenated aromatic solvents such as chlorobenzene, o-, m- or p-chlorotoluene, dichlorobenzene, trifluoromethylbenzene; aprotic polar solvents such as dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide; protic polar solvents such as ethanol, propanol, isopropanol, butanol, t-butanol, pentanol, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol; and mixtures thereof.
  • a single or mixture solvent selected from the group consisting of toluene; xylene; ethylbenzene; halogen
  • the reaction is preferably conducted at a temperature of 90 ⁇ 130°C since it is advantageous in achieving a higher conversion rate in a given time.
  • the temperature of 100 ⁇ 120°C is more preferred.
  • the reaction time is preferably 10 ⁇ 30 hours and more preferably 15 ⁇ 24 hours, and may vary according to the starting material.
  • the process of the present invention may further comprise the steps of: protecting the reactive substituent, forming a tetrazole ring, and then removing the corresponding protecting group, by using conventionally known methods for protecting and deprotecting a functional group.
  • pharmaceutically active compounds for treating hypertension or intermediates useful for preparation thereof can be prepared effectively and economically in an environment-friendly manner.
  • Figure 1 represents the X-ray structure of pure Zn(N 3 ) 2 TMEDA which was obtained by purifying the zinc azide complex prepared according to Example 1.
  • Comparative Example 1-1 Method using the isolated zinc azide complex of the present invention
  • HPLC Agilent 1100 series, solvent: TFA 0.1%, acetonitrile(30 ⁇ 100)/water(70 ⁇ 0), flow rate:1.5ml/min., wavelength:225nm, column: CAPCELL PAK C 18 (4.6mm I.D ⁇ 250 mm, 5 ⁇ m, TYPE AQ)
  • n-butanol 1.5L was added into a reactor, and with stirring sodium azide (189.0g) and zinc chloride (200.1g) were added thereto.
  • the reaction mixture was stirred at 100 ⁇ 120°C for 3 hours or more and cooled to room temperature.
  • 2-butyl-4-chloro-5-hydroxymethyl-1-[(2’-cyano-biphenyl-4-yl)-methyl]-imidazole (379.8g) was added thereto, and the mixture was heated again.
  • the reaction was conducted for 24 hours while maintaining the internal temperature as 100 ⁇ 120°C.
  • n-butanol 1.5L was added into a reactor, and with stirring sodium azide (189.0g) and zinc nitrate hexahydrate (445.3g) were added thereto.
  • the reaction mixture was stirred at 100 ⁇ 120°C for 3 hours or more and cooled to room temperature.
  • 2-butyl-4-chloro-5-hydroxymethyl-1-[(2’-cyano-biphenyl-4-yl)-methyl]-imidazole (379.8g) was added thereto, and the mixture was heated again.
  • the reaction was conducted for 24 hours while maintaining the internal temperature at 100 ⁇ 120°C.
  • Example 1-1 The solid compound (35.0g) obtained in Example 1-1 was added to the toluene solution of N-pentanoyl-N-[(2’-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester obtained in Example 6, and the mixture was heated and refluxed for 24 hours or more.
  • the reaction mixture was cooled to 45 ⁇ 55°C, and water (50mL) and 28% ammonia water (50mL) were added thereto for phase separation.
  • the organic layer was washed with 5% brine solution (100mL), and water (50mL) and sulfuric acid (14.8g) were added thereto and stirred at room temperature for 2 hours or more.
  • the mixture was phase-separated and washed with water (50mL), and then water (50mL) and sodium hydroxide (10.0g) were added thereto, and the mixture was stirred at room temperature for 12 hours or more.
  • stirring was stopped and phase separation was conducted, and then dichloromethane (100mL) was added to the aqueous layer obtained through phase separation.
  • a solution of sulfuric acid (24.5g) diluted in water (50mL) was added thereto at room temperature, and the mixture was stirred for 1 hour.
  • An organic layer was obtained by phase separation and then washed twice with water (50mL).
  • n-hexane (150mL) was slowly added thereto and the mixture was stirred at room temperature for 20 hours or more.
  • the generated solid was filtered, washed with n-hexane (50mL) and dried to obtain the title compound (38.7g).
  • the organic layer was washed with 5% brine solution (100mL), and water (100mL) and sulfuric acid (19.6g) were added thereto and stirred at room temperature for 2 hours or more.
  • the mixture was phase-separated and washed with water (100mL), and then water (100mL) and sodium hydroxide (20.0g) were added thereto, and the mixture was stirred at room temperature for 12 hours or more for phase separation.
  • dichloromethane (200mL) and a solution of sulfuric acid (29.4g) diluted in water (100mL) were added to the aqueous layer obtained through phase separation at room temperature, and the mixture was stirred for 1 hour.
  • the obtained organic layer was washed with water (20mL), and stirred for 1 hour or more with maintaining pH 2 ⁇ 3 by using water (20mL) and sulfuric acid. Phase separation was conducted, the obtained organic layer was concentrated and dissolved by adding thereto THF (20mL) and water (10mL), and then LiOH (0.85g) was added thereto and the reaction was conducted at 25°C. After the completion of the reaction was confirmed by HPLC, the reaction mixture was neutralized with 1N-HCl and the generated solid was filtered to obtain the title compound (3.6g).

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

Abstract

La présente invention concerne un nouveau complexe d'azide de zinc. La présente invention concerne également un procédé de préparation de dérivés de 1H-tétrazole 5-substitué à partir de dérivés nitriles à l'aide du complexe d'azide de zinc. Selon la présente invention, en particulier des composés pharmaceutiques actifs, pour le traitement de l'hypertension, ou des intermédiaires utiles pour la préparation de ceux-ci, peuvent être préparés efficacement.
PCT/KR2012/003135 2011-04-25 2012-04-24 Nouveau complexe d'azide de zinc et procédé de préparation de dérivés de tétrazole l'utilisant Ceased WO2012148148A2 (fr)

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KR20110038664 2011-04-25
KR10-2011-0038664 2011-04-25

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WO2012148148A2 WO2012148148A2 (fr) 2012-11-01
WO2012148148A3 WO2012148148A3 (fr) 2013-01-03
WO2012148148A9 true WO2012148148A9 (fr) 2013-02-14

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CN109761924B (zh) * 2019-02-26 2020-09-01 安徽美诺华药物化学有限公司 一种改进的缬沙坦反应混合液的后处理方法
CN112079788A (zh) * 2019-06-13 2020-12-15 安徽美诺华药物化学有限公司 一种缬沙坦的制备方法
CN110467604B (zh) * 2019-08-29 2020-09-08 浙江天宇药业股份有限公司 一种氯沙坦的制备方法
EP3939967A1 (fr) 2020-07-15 2022-01-19 KRKA, d.d., Novo mesto Procédé continu pour la préparation de (s)-méthyl n-((2'-cyano-[1,1'-biphényl]-4-yl)méthyl)-n-pentanoylvalinate dans un réacteur à écoulement
CN113501831B (zh) * 2021-07-15 2022-11-15 西安近代化学研究所 一种5-氨基四氮唑锌配合物、合成方法及应用
CN116375687A (zh) * 2021-12-22 2023-07-04 浙江华海药业股份有限公司 一种高纯度的氯沙坦钾及其制备方法

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JPH08325248A (ja) * 1995-05-26 1996-12-10 Chugoku Kayaku Kk テトラゾール類の新規な合成試薬及びそれを用いたテトラゾール類の製造方法
GB0316546D0 (en) * 2003-07-15 2003-08-20 Novartis Ag Process for the manufacture of organic compounds
CN101774975B (zh) * 2009-12-25 2012-11-28 中国科学院过程工程研究所 一种离子液体催化的环合反应方法

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WO2012148148A2 (fr) 2012-11-01
KR20120120907A (ko) 2012-11-02
WO2012148148A3 (fr) 2013-01-03
KR101942064B1 (ko) 2019-01-24

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