WO2018210633A1 - Procédé pour la préparation de phénylguanidines ou de leurs sels - Google Patents

Procédé pour la préparation de phénylguanidines ou de leurs sels Download PDF

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Publication number
WO2018210633A1
WO2018210633A1 PCT/EP2018/061878 EP2018061878W WO2018210633A1 WO 2018210633 A1 WO2018210633 A1 WO 2018210633A1 EP 2018061878 W EP2018061878 W EP 2018061878W WO 2018210633 A1 WO2018210633 A1 WO 2018210633A1
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Prior art keywords
cyanamide
range
aniline
formula
containing mixture
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PCT/EP2018/061878
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German (de)
English (en)
Inventor
Thomas GÜTHNER
Original Assignee
Alzchem Trostberg Gmbh
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Publication date
Application filed by Alzchem Trostberg Gmbh filed Critical Alzchem Trostberg Gmbh
Priority to EP18724817.4A priority Critical patent/EP3621952A1/fr
Publication of WO2018210633A1 publication Critical patent/WO2018210633A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
    • C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups

Definitions

  • the present invention relates to a process for the preparation of
  • Phenylguanidines or their salts by an electronegativly substituted aniline is reacted with a cyanamide-containing mixture.
  • Phenylguanidines find versatile use as intermediates in the synthesis of chemical agents, in particular for the production of
  • Phenylguanidines substituted with electronegative radicals. Examples are the published syntheses of the active pharmaceutical ingredients imatinib, nilotinib, dapivirin and etravirine.
  • Non-electronegative substituted phenylguanidines are relatively simple and unproblematic by reacting the corresponding aniline derivative with
  • aniline which is between the values pKs and (pKs -1) of the corresponding aniline, i. for reaction with cyanamide, the aniline is protonated to about 50 to 90% to an ammonium salt.
  • Phenylguanidine salts in aqueous or alcoholic-aqueous solution are suitable to produce the desired products in sufficient yield and - after most necessary recrystallization - of sufficient purity. Due to the high input costs of the respective Anilinderivate, the high cost of a large cyanamide excess and the need for disposal
  • the invention therefore an object of the invention to provide a process for the preparation of electronegativsubstituted Phenylguanidinsalzen which does not have the disadvantages of the prior art, but a high conversion and high yield based on the aniline derivative used, without a large excess of Cyanamide use.
  • a process for the preparation of a phenylguanidine according to formula (Ia) or a phenylguanidine salt according to formula (Ib) is the subject of the present invention in which an electronegatively substituted aniline according to formula (II) is reacted with a cyanamide-containing mixture, where for formulas (Ia), (Ib) and (II):
  • R 1 hydrogen or alkyl, independently of one another are hydrogen, nitro, cyano, methylsulfonyl or a radical of the formulas (III) or (IV), where at least one radical R 2 or R 3 does not denote hydrogen,
  • the electronegatively substituted aniline is reacted with a cyanamide-containing mixture consisting of cyanamide and chloroformamidine hydrochloride in a polar aprotic solvent.
  • a polar aprotic solvent is understood to mean a solvent which has a relative permittivity ⁇ ⁇ (also known as relative dielectric constant) greater than 5.0 (at 25 ° C.), preferably from 6.0 to 60 (at 25 ° C), most preferably from 7.0 to 40 (at 25 ° C), and that no acidic protons, ie, OH, NH or SH functions with an acidity constant pK s (at 25 ° C) with respect having the release of the proton in the range of 0 to 20.
  • ⁇ ⁇ also known as relative dielectric constant
  • the process according to the invention can preferably be carried out in an anhydrous, polar aprotic solvent. It is in the
  • an anhydrous polar aprotic solvent means any solvent or mixture of such solvents which falls within the above definition and which is substantially free of water and production-related less than 1.0% by weight of water, in particular less than 0.5% by weight of water, more preferably less than 0.2% by weight of water and most preferably no water.
  • an electronegatively substituted aniline of the formula (II) is to be understood as meaning an aniline derivative whose pK s value (at 25 ° C.) is in the range from -1 to 3.9, in particular in the range from 0 to 3.5, and most preferably in the range of 0 to 3.0, is located.
  • the pKs value of the aniline should be understood as meaning the pKs value which is the negative decadal
  • a linear or branched alkyl radical with a chain length of up to 10 is furthermore to be understood by alkyl
  • Carbon atoms, in particular of 1 to 6 carbon atoms, be understood, in particular the general formula C n H 2 n + i, wherein n an integer from 1 to 10, in particular an integer from 1 to 6, means.
  • alkyl is methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3 Methylbutyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2,2-dimethylpropyl or 1-ethylpropyl or n-hexyl.
  • alkyl particularly preferably means methyl, ethyl, 1-methylethyl, n-propyl, n-butyl, 2-methylbutyl or 1, 1-dimethylethyl. Most preferably, alkyl according to the present invention means methyl or ethyl.
  • aryl is a monovalent aromatic radical having in particular 3 to 20 carbon atoms, preferably 6 to 20
  • Carbon atoms more preferably 6 carbon atoms, which may be monocyclic, bicyclic or polycyclic.
  • aryl according to the present Invention, in particular phenyl, naphthyl, anthryl, phenantryl, pyrenyl or perylenyl.
  • aryl particularly preferably denotes phenyl.
  • R 1 hydrogen or methyl
  • R 2 , R 3 independently of one another hydrogen, nitro or a radical of the formula
  • R 4 methyl, ethyl, 1-methylethyl, n-propyl, n-butyl, 2-methylbutyl or
  • Guanylating agents e.g., aqueous cyanamide solutions greatly facilitate the reaction of said electronegatively substituted aniline derivatives, such that high conversion rates and good yields are obtainable with low reagent excess and in a simple manner.
  • Aniline derivative in a polar, aprotic solvent, in particular in an anhydrous polar aprotic solvent, with a cyanamide-containing mixture consisting of chloroformamidine hydrochloride and cyanamide,
  • Chloroformamidine hydrochloride and cyanamide reacted Chloroformamidine hydrochloride and cyanamide reacted. Chloroformamidine hydrochloride, cyanamide, a reagent, solvent or mixture having a water content of less than 1% by weight, preferably less than 0.5% by weight, are to be used under anhydrous chloroformamidine hydrochloride, anhydrous cyanamide, anhydrous reagent, solvent or mixture. %, more preferably less than 0.2% by weight.
  • the resulting in high yield and purity electronegative substituted phenylguanidine hydrochloride is generally not crystallizable and therefore difficult to isolate or clean.
  • a guanidine base or by Umsalzen in a more suitable salt, preferably in a nitrate, sulfate, Hydogensulfat-, carbonate or bicarbonate salt in one or more protic or aprotic solvents, the product in a more manageable, in crystalline form isolatable and better to be purified derivative to be converted.
  • a method of the present invention in which the aniline and the cyanamide-containing mixture in the polar aprotic solvent, in particular in the anhydrous polar aprotic solvent, are reacted and subsequently the resulting reaction mixture i) with an alkali, alkaline earth or
  • Ammonium salt or ii) is added to an alkali or alkaline earth metal hydroxide.
  • the process can be carried out by the cyanamide-containing mixture in the polar aprotic solvent, in particular in the anhydrous polar aprotic solvent, submitted and / or the aniline of formula (II) dissolved in the polar aprotic solvent, in particular in the anhydrous polar aprotic solvent, is metered.
  • the process of the invention is suitable for converting electronegatively substituted aniline derivatives having a pKa of from -1 to 3.9, preferably from 0 to 3.5, into the corresponding phenylguanidine derivatives.
  • Electron-negative substituted aniline derivatives are those aniline derivatives which have one or two electron-withdrawing substituents on the benzene ring, namely nitro, cyano, alkylcarbonyl, arylcarbonyl,
  • Suitable polar aprotic solvents for the process of the invention are in particular solvents selected from the group of
  • Halocarbons, ethers, nitriles, ketones, esters, amides, sulfoxides, sulfones are, in particular, solvents from the group consisting of alkylcarboxylic acid esters, dialkyl carbonates, ⁇ , ⁇ -dialkylamides, N-alkyllactams, alkyl- or arylnitriles,
  • Dialkyl sulfoxides and dialkyl sulfones are particularly suitable solvents.
  • Particularly suitable solvents are ethyl acetate, n-butyl acetate, N-methylpyrrolidone, N-methylcaprolactam, acetonitrile, propionitrile, butyronitrile, benzonitrile, diethyl ether, diisopropyl ether, di-n-butyl ether, methyl t-butyl ether, ethyl t-butyl ether, Methyl cyclopentyl ether, tetrahydrofuran, 2-methyl-tetrahydrofuran, tetrahydropyran, dioxane, ethylene glycol dimethyl ether, dichloromethane, trichloromethane, 1, 1, 2-trichloroethene, 1, 1, 2,2-tetrachloroethene,
  • the electronegatively substituted aniline of the formula (II) is selected from a cyanamide-containing mixture
  • a method of the invention comprises in which the cyanamide-containing mixture is used in an amount such that i) the molar ratio of aniline to cyanamide, in particular the molar ratio of aniline to anhydrous cyanamide, in the range from 1: 0.33 to 1: 1, 5, in particular in the range of 1: 0.33 to 1: 1, 2, in particular in the range of 1: 0.5 to 1: 1, 2, in particular in the range of 1 : 0.5 to 1: 1 and most preferably in the range of 1: 0.5 to 1: 0.9, and / or ii) the molar ratio of aniline to chloroformamidine hydrochloride, in particular the molar ratio of aniline to anhydrous chloroformamidine Hydrochloride, in the range from 1: 0.5 to 1: 1, 5, in particular in the range from 1: 0.5 to 1: 1, 2, in particular in the range from 1: 0.5 to 1: 1, 2, in particular in the range from 1: 0.5 to 1: 1 and very particularly
  • chloroformamidine hydrochloride and cyanamide especially the sum of anhydrous chloroformamidine hydrochloride and anhydrous
  • Cyanamide based on 1 mol of aniline, is preferably from 1.0 to 3.0 mol, in particular from 1.0 to 2.0 mol and very particularly preferably from 1.05 to 1.5 mol.
  • a method of the invention comprises in which the aniline of formula (II) with the cyanamide-containing mixture in a molar ratio of aniline to cyanamide-containing mixture in the range of 1: 1 to 1: 3 , in particular in the range of 1: 1 to 1: 2, preferably in the range of 1: 1 to 1: 1, 5, and most preferably in the range of 1: 1, 05 to 1: 1, 5 is reacted.
  • the molar ratio of chloroformamidine hydrochloride to cyanamide, in particular the molar ratio of anhydrous chloroformamidine hydrochloride to anhydrous cyanamide, in the cyanamide-containing mixture is preferably in the range from 2: 1 to 1: 2, particularly preferably from 2: 1 to 1: 2, more preferred from 1: 1, 4 to 1, 4: 1, more preferably from 1, 2: 1 to 1: 1, 2 and most preferably from 1, 1: 1 to 1: 1, 1.
  • a method of the invention comprises in which the cyanamide-containing mixture cyanamide and
  • Anhydrous cyanamide used preferably has a content of at least 98% by weight, at most 1% by weight of water and at most 1% by weight of dicyandiamide.
  • Chloroformamidine hydrochloride may be prepared by known methods, e.g. According to DE 1915668, be prepared from anhydrous cyanamide and anhydrous hydrogen chloride. It preferably has a content greater than 98% by weight and a water content of less than 1% by weight. More preferably, it has a content greater than 99 wt .-% and a water content less than 0.2 wt .-%.
  • chloroformamidine hydrochloride can be prepared from anhydrous cyanamide, this can also in situ by partial reaction of anhydrous
  • Cyanamid be prepared with hydrogen chloride gas in a suitable solvent.
  • a suitable solvent Particularly suitable is the respectively selected anhydrous, polar aprotic solvent, which was selected for the subsequent reaction with the aniline.
  • reaction of the electronegatively substituted aniline of formula (II) and the cyanamide-containing mixture consisting of chloroformamidine hydrochloride and cyanamide in a polar aprotic solvent can be carried out in a wide temperature and pressure range, the reaction times are chosen so that a possible complete reaction is achieved. Typically, the reaction is carried out at a temperature in the range of 0 to 180 ° C,
  • the electronegatively substituted phenyl guanidine hydrochlorides obtained from the reaction are not isolated according to the process of the invention, but further reacted by liberation of the guanidine base of the formula (Ia) or by salification to give a guanidine salt of the formula (Ib).
  • This has the advantage that only in this way well crystallizing, sufficiently poorly soluble products can be obtained, which allow filtration, washing and cleaning of the products, so that the guanidine derivatives to be produced can be obtained in sufficient purity.
  • the precipitation as Guanidinbase can be carried out in a protic solvent, preferred for this process step is water or C1 to C4 alcohols.
  • a protic solvent preferred for this process step is water or C1 to C4 alcohols.
  • the electronegatively substituted phenyl guanidine hydrochlorides prepared by the above process are reacted with an alkali metal hydroxide, the phenylguanidine crystallizing out as the free base and the alkali dissolving as the chloride.
  • this step is carried out in aqueous solution.
  • Preferred alkali metal hydroxides are NaOH or sodium hydroxide solution and KOH or potassium hydroxide solution.
  • the release as Guanidinbase is preferably carried out at a temperature of -10 to 100 ° C, more preferably at a temperature of 0 to 30 ° C.
  • the salification can be carried out in a protic solvent, preferably for this process step is water or C 1 - to C 4 -alcohols.
  • a protic solvent preferably for this process step is water or C 1 - to C 4 -alcohols.
  • the electronegatively substituted phenyl guanine hydrochlorides prepared by the above process are reacted with an ammonium, alkali metal or alkaline earth metal salt of the respectively desired anion for this purpose.
  • Salination are ammonium nitrate, ammonium sulfate, sodium nitrate, sodium sulfate, sodium carbonate, sodium bicarbonate, potassium nitrate, potassium sulfate,
  • Reaction mixture are left.
  • this step is carried out in aqueous or aqueous organic solution. The wished
  • Phenylguanidine salt precipitates from the reaction mixture in solid form and is separated by filtration, while the salt-coproduct (ammonium, alkali or alkaline earth chloride) remains in solution.
  • the salting is preferably carried out at temperatures of -10 to 100 ° C, more preferably at 10 to 70 ° C.
  • the inventive method thus makes it possible to produce the sparingly soluble, crystalline free base or well crystallizing salts of electronegativsubstituted phenylguanidines in high purity and high yield.
  • the following examples are intended to explain the invention in more detail.
  • Example 1 was repeated analogously, wherein the use ratios of 2-methyl-5-nitroaniline (educt) to chloroformamidine hydrochloride or solid cyanamide or else the solvent used were varied. The corresponding data can be found in Table 2.
  • acetonitrile water content ⁇ 0.1% by weight
  • di-n-butyl ether water content ⁇ 0.05% by weight
  • Example 1 was repeated analogously, wherein the use ratios of 2-methyl-5-nitroaniline (educt) to chloroformamidine hydrochloride or solid cyanamide, the solvent used and the water content of the reaction mixture were varied. The corresponding data can be found in Table 3.
  • the reaction mixture was evaporated to dryness in vacuo and then taken up again in water. The precipitation as nitrate salt was carried out in a known manner.
  • Reaction mixture was stirred at 42 ° C for 16 hours. Then it was evaporated to dryness, taken up in 75 g of water and added dropwise at 57 ° C 22.0 g of a 55 wt .-% - solution of ammonium nitrate in water; The desired product precipitated.
  • the pH of the solution was 2.45 g 25 wt .-% -

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé pour la préparation de phénylguanidines ou de leurs sels consistant en ce qu'une aniline substituée de manière électronégative est amenée à réagir avec un mélange contenant du cyanamide.
PCT/EP2018/061878 2017-05-13 2018-05-08 Procédé pour la préparation de phénylguanidines ou de leurs sels WO2018210633A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP18724817.4A EP3621952A1 (fr) 2017-05-13 2018-05-08 Procédé pour la préparation de phénylguanidines ou de leurs sels

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102017004596.8 2017-05-13
DE102017004596.8A DE102017004596B4 (de) 2017-05-13 2017-05-13 Verfahren zur Herstellung von Phenylguanidinen oder deren Salze

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1915668A1 (de) 1969-03-27 1970-10-08 Sueddeutsche Kalkstickstoff Verfahren zur Herstellung von Halogenformamidiniumhalogeniden
US3931316A (en) 1974-08-10 1976-01-06 Suddeutsche Kalkstickstoff-Werke Ag Method of preparing O-methyl-isourea hydrogen sulfate and O-methyl-isourea sulfate from cyanamide
EP0560726B1 (fr) 1992-03-11 1996-05-29 Ciba-Geigy Ag Procédé pour la préparation de dérivés de la guanidine
DE19719024A1 (de) 1997-05-05 1998-11-12 Sueddeutsche Kalkstickstoff Verfahren zur Herstellung von kristallinem O-Methylisoharnstoff-acetat
US20040248918A1 (en) 2003-05-06 2004-12-09 Il Yang Pharm. Co., Ltd. N-phenyl-2-pyrimidine-amine derivatives and process for the preparation thereof
WO2004108699A1 (fr) 2003-06-06 2004-12-16 Natco Pharma Limited Nouveau procede de preparation du medicament anticancereux imatinibe et de nouveaux analogues de ce medicament
WO2006071130A2 (fr) 2004-12-30 2006-07-06 Instytut Farmaceutyczny Procede de preparation d'une base d'imatinibe
WO2008080965A2 (fr) * 2006-12-29 2008-07-10 Tibotec Pharmaceuticals Ltd. Pymiridines substituées en 5,6, inhibitrices du vih

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1915668A1 (de) 1969-03-27 1970-10-08 Sueddeutsche Kalkstickstoff Verfahren zur Herstellung von Halogenformamidiniumhalogeniden
US3931316A (en) 1974-08-10 1976-01-06 Suddeutsche Kalkstickstoff-Werke Ag Method of preparing O-methyl-isourea hydrogen sulfate and O-methyl-isourea sulfate from cyanamide
EP0560726B1 (fr) 1992-03-11 1996-05-29 Ciba-Geigy Ag Procédé pour la préparation de dérivés de la guanidine
DE19719024A1 (de) 1997-05-05 1998-11-12 Sueddeutsche Kalkstickstoff Verfahren zur Herstellung von kristallinem O-Methylisoharnstoff-acetat
US20040248918A1 (en) 2003-05-06 2004-12-09 Il Yang Pharm. Co., Ltd. N-phenyl-2-pyrimidine-amine derivatives and process for the preparation thereof
WO2004108699A1 (fr) 2003-06-06 2004-12-16 Natco Pharma Limited Nouveau procede de preparation du medicament anticancereux imatinibe et de nouveaux analogues de ce medicament
WO2006071130A2 (fr) 2004-12-30 2006-07-06 Instytut Farmaceutyczny Procede de preparation d'une base d'imatinibe
WO2008080965A2 (fr) * 2006-12-29 2008-07-10 Tibotec Pharmaceuticals Ltd. Pymiridines substituées en 5,6, inhibitrices du vih

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
A. KOMPELLA, ORG. PROC. RES. DEV., vol. 16, 2012, pages 1794
IAN ARMITAGE ET AL: "The Use of Chloroformamidine Hydrochloride as a Reagent for the Synthesis of Guanidines from Electron Deficient Aromatic Amines : Chloroformamidine HCl as a Reagent for the Synthesis of Guanidines", JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 54, no. 1, 27 November 2015 (2015-11-27), US, pages 728 - 734, XP055480913, ISSN: 0022-152X, DOI: 10.1002/jhet.2567 *
ISMAIL ABDILLAHI ET AL: "Synthesis of a Novel Series of Thieno[3,2-d]pyrimidin-4-(3H)-ones", SYNTHESIS, vol. 2010, no. 09, 1 May 2010 (2010-05-01), pages 1428 - 1430, XP055065803, ISSN: 0039-7881, DOI: 10.1055/s-0029-1218697 *
L. C. CHAN, ORG. PROC. RS. DEV., vol. 11, 2007, pages 981
W. DERMAUT, ICHEME SYMPOSIUM SERIES, no. 153, 2007, pages 1

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DE102017004596B4 (de) 2021-02-11
DE102017004596A1 (de) 2018-11-15
EP3621952A1 (fr) 2020-03-18

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