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WO2024218026A1 - Procédé de préparation de 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile et de ses dérivés - Google Patents

Procédé de préparation de 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile et de ses dérivés Download PDF

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Publication number
WO2024218026A1
WO2024218026A1 PCT/EP2024/060118 EP2024060118W WO2024218026A1 WO 2024218026 A1 WO2024218026 A1 WO 2024218026A1 EP 2024060118 W EP2024060118 W EP 2024060118W WO 2024218026 A1 WO2024218026 A1 WO 2024218026A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
carbonitrile
dihydrothiazole
hydroxy
alkyl
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.)
Pending
Application number
PCT/EP2024/060118
Other languages
English (en)
Inventor
Stefan Hildbrand
Christian Oliver KAPPE
Michael PRIESCHL
Kurt Puentener
Jason Douglas WILLIAMS
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.)
F Hoffmann La Roche AG
Hoffmann La Roche Inc
Original Assignee
F Hoffmann La Roche AG
Hoffmann La Roche 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 F Hoffmann La Roche AG, Hoffmann La Roche Inc filed Critical F Hoffmann La Roche AG
Priority to CN202480021607.XA priority Critical patent/CN120858090A/zh
Publication of WO2024218026A1 publication Critical patent/WO2024218026A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/14—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the invention relates to a novel process for the preparation of 4-hydroxy-4,5- dihydrothiazole-2-carbonitrile of the formula I comprising, reacting cyanogen with l,4-dithiane-2,5-diol of the formula II in a polar aprotic solvent in the presence of a tertiary organic amine.
  • the invention further relates to the transformation of the 4-hydroxy-4,5- dihydrothiazole-2-carbonitrile of the formula I into the versatile precursor compound thiazole-2-carbonitrile of the formula III -hydroxy-4,5-dihydrothiazole-2-carbonitrile derivatives of the formula IV thiazole-2-carboximidamide of formula V or of a salt thereof
  • the invention comprises the novel thiazole precursor
  • R 1 is Ci-6-alkyl or phenyl, wherein the phenyl ring is optionally substituted with, halogen, Ci-6-alkyl or Ci-6-alkoxy.
  • Thiazole core structures form the scaffold of many lead compounds in drug discovery (A. Ayati et al, European Journal of Medicinal Chemistry 97 (2015), 699-718).
  • PCT International Publication WO 2015/132276 Al discloses 6-fused heteroaryl dihydropyrimidines, which carry a thiazole moiety in the core structure and which have a potential to be used in the treatment and prophylaxis of Hepatitis B infections.
  • Object of the invention was to find a scalable processes for producing the precursor compound 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile of the formula I from starting products available on a large scale and processes for the further transformation into the thiazole derivatives of formula III, IV and V as outlined above.
  • Ci-6-alkyl denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms. Typical examples include methyl, ethyl and propyl, butyl, pentyl or hexyl with its isomers, preferably Ci-4-alkyl, more preferably methyl or ethyl.
  • Ci-6-alkoxy denotes a Ci-6-alkyl group as defined above, which is attached to an oxygen atom. Typical examples include methoxy, ethoxy and propyloxy, butyloxy, pentyloxy or hexyloxy with its isomers, preferably Ci-4-alkyloxy, more preferably methoxy or ethoxy.
  • halogen stands for a halogen atom, which includes fluorine, chlorine, bromine and iodine, preferably chlorine.
  • HO comprises, reacting cyanogen with l,4-dithiane-2,5-diol of the formula II
  • Cyanogen is a gas which is commercially available. For large scale applications it can be directly fed to the reaction mixture.
  • cyanogen can also be generated in situ by adding an aqueous solution of an alkali metal cyanide to an aqueous solution of a copper (II) salt having a temperature of 60°C to 100°C, preferably at about 80°C.
  • Suitable copper (II) salt is copper (II) sulfate and a suitable alkali metal cyanide is sodium- or potassium cyanide, preferably sodium cyanide.
  • the generated cyanogen can be directly delivered to the mixture of l,4-dithiane-2,5- diol of the formula II, tertiary organic amine and polar aprotic solvent having a temperature of 20°C to 80°C, preferably 30°C to 70°C.
  • the cyanogen is applied of 1.0 equivalents to 10.0 equivalents, preferably of 3.0 equivalents to 5.0 equivalents related to 1.0 equivalent of l,4-dithiane-2,5-diol.
  • the aprotic solvent can be selected from Ci-4-alkyl acetates such as ethyl acetate or isopropyl acetate, but preferably is ethyl acetate.
  • the tertiary organic amine typically is a tri-Ci-4-alkylamine such as diisopropylethyl amine or triethylamine.
  • the resulting 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile of the formula I can be isolated, but in a preferred embodiment is kept in the reaction solution and further transformed, without its isolation in the subsequent process variants a) or b).
  • HO is a compound which has not been described before and therefore constitutes a preferred embodiment of the present invention.
  • the 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile of the formula I can be transformed by way of a dehydration into the thiazole-2-carbonitrile of the formula III.
  • Suitable dehydrating agents are selected from tri-Cm- alkyl silyl halogenides, such as trimethylsilyl chloride, mineral acids such as hydrochloric acid or sulfuric acid, organic acids and its halogenides, such as acetic acid, -toluene sulfonic acid or methanesulfonyl chloride or phosphoric acid derivatives such as phosphorous oxychloride or phosphorous pentoxide.
  • Preferred dehydrating agents are methanesulfonyl chloride or trimethylsilyl chloride, more preferably trimethylsilyl chloride.
  • the dehydrating agent can be applied in a range of 0.2 equivalents to 5.0 equivalents, preferably 0.5 equivalents to 1.5 equivalents related to 1.0 equivalent of 4-hydroxy-4,5- dihydrothiazole-2-carbonitrile.
  • the reaction ideally takes place in the polar aprotic solvent of the previous reaction step which preferably is ethyl acetate. It is however possible to work in a suitable alternative solvent, such as in a lower aliphatic alcohol, like ethanol.
  • a reaction temperature between 20°C and 100°C, preferably between 30°C and 70°C is usually chosen.
  • the thiazole-2-carbonitrile can be isolated by quenching the reaction mixture with water and recovering the product from the organic phase by methods well known to the skilled in the art. Further purification of the crude product can be achieved by sublimation.
  • the crude thiazole-2-carbonitrile is, without further purification, further transformed into the thiazole-2-carboximidamide of formula V or of a salt thereof.
  • the reaction involves in a first step a treatment with a base, which typically is an alkali alcoholate, preferably sodium methylate.
  • a base typically is an alkali alcoholate, preferably sodium methylate.
  • This reaction steps forms an intermediary iminoether, which, without isolation, is reacted further with the addition of ammonia or of an ammonium salt.
  • an ammonium salt is added, which can be selected from an ammonium salt of a mineral acid, such as e.g. from hydrochloric acid or from an organic acid such as e.g. from acetic acid or methane sulfonic acid.
  • Preferred ammonium salts therefore are ammonium chloride, ammonium acetate or ammonium mesylate, but more preferably is ammonium chloride.
  • the reaction can be carried out at a reaction temperature between -10°C and 10°C, preferably at about 0°C in a polar protic solvent, such as in an aliphatic alcohols, preferably in methanol.
  • a polar protic solvent such as in an aliphatic alcohols, preferably in methanol.
  • the product can be recovered from the reaction mixture by removing the solids by filtration and subsequently by distilling off the polar protic solvent and crystallizing the crude with a polar aprotic solvent such as MeCN and water
  • the 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile of the formula I is acylated with an acyl halide R ’COX or an acid anhydride R 1 C-(O)O(O)C-R 1 , wherein R 1 is Ci-6-alkyl or phenyl, wherein the phenyl ring is optionally substituted with, halogen, Ci-6-alkyl or Ci-6-alkoxy, to form 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile derivatives of the formula IV wherein R 1 is as above.
  • Suitable acyl halides R x COX are those with R 1 is Ci-4-alkyl, particularly methyl or phenyl and with X is chlorine.
  • Preferred acyl halides are acetyl chloride or benzoyl chloride.
  • Suitable acid anhydride R 1 C-(O)O(O)-CR 1 are those with R 1 is Cw-alkyl, particularly methyl or phenyl.
  • Preferred acid anhydride is acetic anhydride.
  • the reaction is preferably carried out in the presence of a tertiary organic amine, typically a tri-Ci-4-alkylamine such as tri ethylamine.
  • a tertiary organic amine typically a tri-Ci-4-alkylamine such as tri ethylamine.
  • the reaction can take place at a reaction temperature between -10°C and 100°C, preferably at about 50°C in the polar aprotic solvent of the previous reaction step.
  • HPLC analysis were carried out on a Shimadzu instrument using a Cl 8 reversed-phase analytical column (150 mm x 4.6 mm, particle size 5 pm) using mobile phases A (H 2 O/MeCN 90:10 (v/v) + 0.1 % CF3COOH) and B (MeCN + 0.1 % CF3COOH) at a flow rate of 1.5 mL/min. Retention times: 2.74 min (2), 7.72 min (3), 10.71 min (4), 4.54 min (5), 1.07 min (6) - applying the following gradient program for mobile phase B in A (% v/v):
  • GC-FID Analysis was performed on a Shimadzu GC FID 230 with a flame ionization detector, using an RTX-5MS column (30 m x 0.25 mm ID x 0.25 pm) and helium as carrier gas (40 cm sec -1 linear velocity).
  • the injector temperature was set to 280°C. After 1 min at 50°C, the temperature was increased by 25°C/min to 300°C and kept constant at 300°C for 4 min.
  • the detector gases used for flame ionization were hydrogen and synthetic air (5.0 quality). Retention times: 5.94 min (2), 4.53 min (5)
  • the desired product (5) was quantified as 67.5% NMR assay yield using 1,3, 5 -trimethoxy benzene as internal standard.
  • the crude title compound 5 was purified by sublimation (60°C/15 mbar) to afford 835 mg (37% yield) product as colorless crystals.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un nouveau procédé de préparation de 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile de formule (I), (I). Le 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile est un intermédiaire polyvalent qui peut être utilisé pour préparer des composés précurseurs polyvalents de composés pharmaceutiquement actifs, tels que des médicaments et d'autres composés chimiques utilisés en médecine. L'invention concerne en outre la transformation du 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile de formule I en thiazole-2-carbonitrile de formule (III), (III), le thiazole-2-carboximidamide de formule (V), ou un sel de celui-ci, la formule (V), (V) et les dérivés de 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile de formule (IV), (IV), -26- où R1 est un alkyle en C1-6 ou phényle et le cycle phényle étant éventuellement substitué par, halogène, alkyle en C1-6 ou alcoxy en C1-6.
PCT/EP2024/060118 2023-04-17 2024-04-15 Procédé de préparation de 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile et de ses dérivés Pending WO2024218026A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202480021607.XA CN120858090A (zh) 2023-04-17 2024-04-15 用于制备4-羟基-4,5-二氢噻唑-2-甲腈及其衍生物的方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP23168155 2023-04-17
EP23168155.2 2023-04-17

Publications (1)

Publication Number Publication Date
WO2024218026A1 true WO2024218026A1 (fr) 2024-10-24

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Country Status (3)

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CN (1) CN120858090A (fr)
TW (1) TW202506652A (fr)
WO (1) WO2024218026A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1555257A1 (fr) * 2002-10-21 2005-07-20 IHARA CHEMICAL INDUSTRY Co., Ltd. Procede permettant de produire un compose de nitrile aromatique
WO2013060744A2 (fr) * 2011-10-25 2013-05-02 Universite De Droit Et De La Sante De Lille 2 Composés présentant une activité d'inhibition d'ethr, utilisation desdits composés en tant que médicaments, composition pharmaceutique et produit contenant lesdits composés
WO2015132276A1 (fr) 2014-03-07 2015-09-11 F. Hoffmann-La Roche Ag Nouvelles héteroaryldihydropyrimidines condensées en position 6 pour le traitement et la prophylaxie d'une infection à virus de l'hépatite b

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1555257A1 (fr) * 2002-10-21 2005-07-20 IHARA CHEMICAL INDUSTRY Co., Ltd. Procede permettant de produire un compose de nitrile aromatique
WO2013060744A2 (fr) * 2011-10-25 2013-05-02 Universite De Droit Et De La Sante De Lille 2 Composés présentant une activité d'inhibition d'ethr, utilisation desdits composés en tant que médicaments, composition pharmaceutique et produit contenant lesdits composés
WO2015132276A1 (fr) 2014-03-07 2015-09-11 F. Hoffmann-La Roche Ag Nouvelles héteroaryldihydropyrimidines condensées en position 6 pour le traitement et la prophylaxie d'une infection à virus de l'hépatite b

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
A. AYATI ET AL., EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 97, 2015, pages 699 - 718
LIBMAN D. D. ET AL: "Congeners of Pyridine-4-carboxyhydraxide. Part I. Derivatives of 4-Cyanopyridine and 2-Cyanothiazole.", J. CHEM. SOC., 1 January 1956 (1956-01-01), pages 2253 - 2257, XP093078393 *
THOMAS SCHAREINA ET AL: "A State-of-the-Art Cyanation of Aryl Bromides: A Novel and Versatile Copper Catalyst System Inspired by Nature", CHEMISTRY - A EUROPEAN JOURNAL, JOHN WILEY & SONS, INC, DE, vol. 13, no. 21, 7 May 2007 (2007-05-07), pages 6249 - 6254, XP071826415, ISSN: 0947-6539, DOI: 10.1002/CHEM.200700079 *

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CN120858090A (zh) 2025-10-28
TW202506652A (zh) 2025-02-16

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