EP1910251A1 - Verfahren zur reindarstellung von 5-substituierten tetrazolen - Google Patents
Verfahren zur reindarstellung von 5-substituierten tetrazolenInfo
- Publication number
- EP1910251A1 EP1910251A1 EP06760815A EP06760815A EP1910251A1 EP 1910251 A1 EP1910251 A1 EP 1910251A1 EP 06760815 A EP06760815 A EP 06760815A EP 06760815 A EP06760815 A EP 06760815A EP 1910251 A1 EP1910251 A1 EP 1910251A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- phase
- general formula
- organic
- water
- nitrile
- 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.)
- Withdrawn
Links
Classifications
-
- 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
-
- 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
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Definitions
- 5-substituted tetrazoles can be prepared by reacting cyano compounds or nitriles with azides and here again in addition to HN 3 with alkali metal or alkaline earth metal azides or organotin azides, such as trialkyl or triaryltin azides.
- the EP 443983 Al are here in connection with the production of sartans as the preferred reaction with sodium or potassium azide and triethyl or Tributylzinnaziden or Triphenylzinnaziden refer.
- the process according to the invention consists essentially in the fact that the organic phases containing the nitrile and the tetrazole are first mixed with water to form three liquid phases, followed by the aqueous phase containing the azide and the upper phase containing the nitrile separated and the middle of the tetrazole-containing organic phase is further treated, wherein in the case of esterified groups to be saponified this phase with alkali, then the organic phase is separated and the aqueous phase is acidified or otherwise this phase is directly acidified and purified.
- the 5-substituted tetrazoles fulfill certain prerequisites with regard to hydrophilic and lipophilic substituents, and in particular if they are substituted biphenyl radicals on the 5-substituted tetrazoles, it is possible that after the reaction of the azide with the nitrile in the presence of amine salts, such as triethylamine hydrochloride, is not directly hydrolyzed, but first water is added to form three liquid phases.
- amine salts such as triethylamine hydrochloride
- the organic liquid phases are the solvent and again, in particular, an aromatic solvent, in particular toluene, xylene or mesitylene, this solvent naturally being the unreacted starting material, namely the corresponding nitrile, as well as impurities, as far as they are concerned are soluble in this solvent.
- the water-soluble constituents of the reaction mixture and in particular the originally solid phase are found in the aqueous phase, which now contains unreacted sodium azide and, for example, triethylamine hydrochloride. Between these two phases, an increasing middle phase now forms with the organic solvent, which contains the desired product, namely the 5-substituted tetrazole in high concentration.
- This step which precedes further purification or, if necessary, the hydrolysis step, in which the mixture is mixed with water, thus makes it possible to carry out a high degree of prepurification in a particularly simple manner, in which unreacted azides in particular can be discharged with the aqueous phase.
- the middle organic phase can subsequently be mixed with alkali metal hydroxide, as proposed according to the invention so as to effect saponification or hydrolysis, depending on the nature of the substituents, if the compound present in the middle organic phase is not the final product.
- the 5-substituted tetrazoles are preferably compounds of the general formula I in which R represents a substituted biphenyl radical.
- Particularly preferred according to the invention are the specifically defined compounds valsartan, losartan, irbesartan, candesartan and olmesartan.
- the nitrile is N-valeryl-N- [(2'-cyanobiphenyl-4-yl) methyl] - (L) -valine methyl ester, which of course must be subsequently saponified to give the final pro -, namely, (S) -N- (1-carboxy-2-methyl-prop-1-yl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl ] -amin to arrive.
- the middle organic phase containing the highly concentrated and as a rule still esterified product is subjected to hydrolysis or saponification with aqueous or ethanolic potassium hydroxide solution or sodium hydroxide solution, whereupon an organic phase and an aqueous phase are formed ,
- the largely aqueous lower phase is further treated in the sequence and now contains the hydrolyzed or hydrolyzed whereas the upper phase containing the selected solvent, for example toluene, xylene or mesitylene, is discarded.
- the separated aqueous phase is preferably subsequently treated with an organic solvent, preferably lower alkyl acetate, such as methyl acetate, ethyl acetate or butyl acetate, and acidified. It is thus essential here that this aqueous phase no longer contains any acids, whereupon branched or cyclic hydrocarbons and / or ethers, in particular methylcyclohexane and / or diisopropyl ether, are added with heating.
- a ratio of 1-2 of acetic acid ester to the subsequently added branched or cyclic hydrocarbon or diisopropyl ether has proven useful here.
- the organic phase is treated further and water is completely separated by means of a water separator.
- Complete removal of water is a prerequisite for obtaining a partially crystalline, filterable product in the subsequent crystallization process. Even small amounts of water would lead here to a two-phase system in which the product settles as a second liquid phase and can not be filtered. After cooling and crystallization of the product, the product can be easily separated by filtration and dried.
- K 2 CO 3 (110 g) is dissolved in water (250 ml). Then toluene (800 ml) and N- [(2'-cyanobiphenyl-4-yl) methyl-3 (L) -valine methyl ester (100 g) are added and stirred vigorously at room temperature until all the solid has dissolved ( about 30 minutes).
- Valeroyl chloride (44 ml) is added dropwise at T ⁇ 20 ° C. The mixture is then stirred for 1.5 to 2.0 hours at 20 to 25 ° C. Salts that precipitate during the reaction are filtered off
- the aqueous phase is separated off, the organic phase is washed with a mixture of 100 ml of brine and 100 ml of water, the washing phase is separated off and discarded.
- the uppermost phase contains unreacted N - [(2'-cyanobiphenyl-4-yl) methyl] (L) -valine methyl ester and N-valeryl-N- [(2'-cyanobiphenyl-4-yl) methyl] - (L) -valine methyl ester and impurities, has a bright appearance and is slightly brownish-yellow;
- the middle phase contains highly concentrated (S) -N- (1-methoxycarboxy-2-methyl-prop-1-yl) -N-pentanoyl-N- [2 '- (1H-tetrazole-5-yl) yl) biphenyl-4-ylmethyl] -arnine solution and is brown in appearance;
- the lower phase (aqueous) contains salts (unreacted sodium azide and triethylamine hydrochloride) and is slightly brownish-yellow in appearance.
- a largely aqueous lower phase ((S) -N- (1-carboxy-2-methyl-prop-1-yl) -N-pentanoyl-N- [2 '- (IH-tetrazol-5-yl) biphenyl-4- ylmethyl] -amine) with a low volume of a toluene upper phase.
- the upper phase is separated and discarded.
- N-Valeryl-N- [(2'-cyanobiphenyl-4-yl) methyl] (L) -valine methyl ester (110 g, 270 mmol) is dissolved in an aromatic hydrocarbon, preferably in toluene, xylenes or mesitylene (typically 500-1000 ml) with alkali metal azides and another reagent (ammonium halide derivatives, typically triethylamine hydrochloride, or organotin halides, typically trimethyltin chloride or tributyltin chloride) with heating to (S) -N- (1-methoxycarboxy-2-methyl-prop-1-yl).
- an aromatic hydrocarbon preferably in toluene, xylenes or mesitylene (typically 500-1000 ml) with alkali metal azides and another reagent (ammonium halide derivatives, typically triethylamine hydrochloride, or organotin halides, typically
- reaction solution is stirred with water or brine (250 ml), whereupon the solid dissolves and forms a three-phase liquid system.
- the lower phase is separated, the two upper phases are washed with water or brine (200 ml).
- the middle phase is isolated and stirred vigorously with aqueous potassium hydroxide solution (2.5 N, 400 ml) at 40 ° C. for 3 h.
- aqueous potassium hydroxide solution 2.5 N, 400 ml
- the result is a two-phase system with. an aqueous, product-containing lower phase and an organic upper phase.
- the aqueous phase is isolated, stirred with 5 g of activated carbon and 5 g of celite for 1 h at 40 ° C, filtered.
- Ethyl acetate (720 ml) is added to the filtrate and acidified to pH 2.0 with vigorous stirring and ice cooling with hydrochloric acid (5-6 N).
- the organic phase is washed with 300 ml of water and, after separation of the washing phase, an aliphatic hydrocarbon or a mixture of aliphatic hydrocarbons (480 ml) is added dropwise, preferably methylcyclohexane or isooctane.
- an aliphatic hydrocarbon or a mixture of aliphatic hydrocarbons (480 ml) is added dropwise, preferably methylcyclohexane or isooctane.
- a water separator the residual water still contained in the system is separated. It is slowly cooled to 5 ° C, whereby crystallization occurs.
- the solid is filtered off, washed with a mixture of ethyl acetate and hydrocarbon and dried at 40 ° C in vacuo. Yield over both stages: about 75% of theory
- reaction solution is stirred with water or brine (250 ml), whereupon the solid dissolves and forms a three-phase liquid system. If only two phases are present, special gasoline 80/110 is added until three well separable phases are formed. The lower phase is separated, the two upper phases are washed with water or brine (200 ml). The middle phase is isolated and washed with potassium hydroxide in ethanol (2.5 N, 400 ml) at 40 ° C for 2 h. Water (400 ml) is added and 500 ml of liquid are distilled off under reduced pressure. With the addition of 5 g of activated carbon and 5 g of Celite is stirred at 40 ° C and filtered for 1 h.
- Ethyl acetate (720 ml) is added to the filtrate and acidified to pH 2.0 with vigorous stirring and ice cooling with hydrochloric acid (5-6 N).
- the organic phase is washed with 300 ml of water and, after separation of the washing phase, an aliphatic hydrocarbon or a mixture of aliphatic hydrocarbons (480 ml) is added dropwise, preferably methylcyclohexane or special gasoline 80/110.
- an aliphatic hydrocarbon or a mixture of aliphatic hydrocarbons (480 ml) is added dropwise, preferably methylcyclohexane or special gasoline 80/110.
- the residual water still contained in the system is separated. It is slowly cooled to 5 ° C, whereby crystallization occurs.
- the solid is filtered off, washed with a mixture of ethyl acetate and hydrocarbon and dried at 40 ° C in a vacuum.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT0131705A AT502219B1 (de) | 2005-08-04 | 2005-08-04 | Verfahren zur reindarstellung von 5-substituierten tetrazolen |
PCT/AT2006/000328 WO2007014412A1 (de) | 2005-08-04 | 2006-08-03 | Verfahren zur reindarstellung von 5-substituierten tetrazolen |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1910251A1 true EP1910251A1 (de) | 2008-04-16 |
Family
ID=37188872
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP06760815A Withdrawn EP1910251A1 (de) | 2005-08-04 | 2006-08-03 | Verfahren zur reindarstellung von 5-substituierten tetrazolen |
Country Status (8)
Country | Link |
---|---|
US (1) | US20090203920A1 (de) |
EP (1) | EP1910251A1 (de) |
JP (1) | JP2009502975A (de) |
KR (1) | KR20080034448A (de) |
CN (1) | CN101253131A (de) |
AT (1) | AT502219B1 (de) |
IL (1) | IL189144A0 (de) |
WO (1) | WO2007014412A1 (de) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100963520B1 (ko) | 2008-02-04 | 2010-06-15 | 일동제약주식회사 | 이르베사르탄의 개선된 제조방법 |
CN102822151B (zh) * | 2010-04-07 | 2015-03-18 | 新梅斯托克公司 | 用于制备缬沙坦的改进的方法 |
WO2012031298A2 (en) | 2010-09-03 | 2012-03-08 | Duke University | Ethynylbenzene derivatives |
WO2015024011A2 (en) | 2013-08-16 | 2015-02-19 | Duke University | Antibacterial compounds |
US10647664B2 (en) | 2013-08-16 | 2020-05-12 | Duke University | Substituted hydroxamic acid compounds |
WO2015024016A2 (en) | 2013-08-16 | 2015-02-19 | Duke University | 2-piperidinyl substituted n,3-dihydroxybutanamides |
CN108752285A (zh) * | 2018-07-13 | 2018-11-06 | 浙江华海药业股份有限公司 | 一种缬沙坦的合成方法 |
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 (de) | 2020-07-15 | 2022-01-19 | KRKA, d.d., Novo mesto | Kontinuierliches verfahren zur herstellung von (s)-methyl-n-((2'-cyano-[1,1'-biphenyl]-4-yl)methyl)-n-pentanoylvalinat n einem strömungsreaktor |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE59107440D1 (de) * | 1990-02-19 | 1996-04-04 | Ciba Geigy Ag | Acylverbindungen |
JP3419819B2 (ja) * | 1993-03-19 | 2003-06-23 | 東洋化成工業株式会社 | 5−(1,1’−ビフエニル)−1h−テトラゾール化合物の製造方法 |
JP3671266B2 (ja) * | 1996-03-21 | 2005-07-13 | 東洋化成工業株式会社 | 5−置換テトラゾール類の製造方法 |
CN100497302C (zh) * | 2002-09-05 | 2009-06-10 | 神经研究公司 | 二芳基脲衍生物和它们作为氯通道阻滞剂的用途 |
-
2005
- 2005-08-04 AT AT0131705A patent/AT502219B1/de not_active IP Right Cessation
-
2006
- 2006-08-03 WO PCT/AT2006/000328 patent/WO2007014412A1/de active Application Filing
- 2006-08-03 EP EP06760815A patent/EP1910251A1/de not_active Withdrawn
- 2006-08-03 JP JP2008524309A patent/JP2009502975A/ja active Pending
- 2006-08-03 US US11/997,372 patent/US20090203920A1/en not_active Abandoned
- 2006-08-03 KR KR1020087002658A patent/KR20080034448A/ko not_active Application Discontinuation
- 2006-08-03 CN CNA2006800289231A patent/CN101253131A/zh active Pending
-
2008
- 2008-01-31 IL IL189144A patent/IL189144A0/en unknown
Non-Patent Citations (1)
Title |
---|
See references of WO2007014412A1 * |
Also Published As
Publication number | Publication date |
---|---|
IL189144A0 (en) | 2008-08-07 |
WO2007014412A1 (de) | 2007-02-08 |
US20090203920A1 (en) | 2009-08-13 |
CN101253131A (zh) | 2008-08-27 |
AT502219B1 (de) | 2007-04-15 |
KR20080034448A (ko) | 2008-04-21 |
JP2009502975A (ja) | 2009-01-29 |
AT502219A1 (de) | 2007-02-15 |
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Legal Events
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AX | Request for extension of the european patent |
Extension state: AL BA HR MK RS |
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RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: OBERLEITNER, WOLFGANG Inventor name: GERDENITSCH, ANTON Inventor name: WELZIG, STEFAN |
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Effective date: 20100212 |