(19) TZZ Z_T

(11) EP 2 874 980 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07B 43/08 (2006.01) C07C 209/50 (2006.01) 22.11.2017 Bulletin 2017/47 C07C 233/65 (2006.01) C07C 235/46 (2006.01) C07C 255/33 (2006.01) C07C 231/02 (2006.01) (2006.01) (2006.01) (21) Application number: 13819917.9 C07C 253/20 C07C 253/30

(22) Date of filing: 18.07.2013 (86) International application number: PCT/IN2013/000447

(87) International publication number: WO 2014/013512 (23.01.2014 Gazette 2014/04)

(54) IMPROVED PROCESS FOR PREPARATION OF 2,3-DIHYDROXY BENZONITRILE VERBESSERTES VERFAHREN ZUR HERSTELLUNG VON 2,3DIHYDROXYBENZONITRIL PROCÉDÉ AMÉLIORÉ POUR LA PRÉPARATION DE 2,3-DIHYDROXYBENZONITRILE

(84) Designated Contracting States: (74) Representative: Hamm & Wittkopp Patentanwälte AL AT BE BG CH CY CZ DE DK EE ES FI FR GB PartmbB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Jungfernstieg 38 PL PT RO RS SE SI SK SM TR 20354 Hamburg (DE)

(30) Priority: 19.07.2012 IN CH29262012 (56) References cited: EP-A1- 2 711 419 GB-A- 967 605 (43) Date of publication of application: JP-A- S54 128 542 27.05.2015 Bulletin 2015/22 • ERGERON, R. J. ET AL.: ’Partition-Variant (73) Proprietor: Laurus Labs Limited Desferrithiocin Analogues: Organ Targeting and Hyderabad 500034 (IN) Increased Iron Clearance.’ J. MED. CHEM. vol. 48, 14 January 2005, pages 821 - 831, XP008122645 (72) Inventors: • STUART J G ET AL: "THE SYNTHESIS OF • MUDDULURU, Hari Krishna DIMETHOXY- AND TRIMETHOXY not 1 3/4 Ranga Reddy District BENZOTHIENOL not 2,3-C 3/4 QUINOLINES", Hyderabad 500078 (IN) JOURNAL OF HETEROCYCLIC CHEMISTRY, • MADHAVARAM, Shankar WILEY-BLACKWELL PUBLISHING, INC, US, vol. Ranga Reddy District 24, 1 November 1987 (1987-11-01), pages Hyderabad 500078 (IN) 1589-1594, XP002949914, ISSN: 0022-152X, DOI: 10.1002/JHET.5570240617

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 874 980 B1

Printed by Jouve, 75001 PARIS (FR) EP 2 874 980 B1

Description

FIELD OF THE INVENTION

5 [0001] The present invention relates to one pot synthesis of 2, 3-dihydroxy benzonitrile from 2, 3-dialkoxy benzoic acid without isolating any intermediates.

BACKGROUND OF THE INVENTION

10 [0002] The substituted catechol compounds have a great commercial importance in the synthesis of pharmaceutical compounds. 2, 3-dihydroxy benzonitrile of Formula I, a substituted catechol compound is an important starting material for the preparation of a number of valuable heterocyclic compounds which are medicinally important. 2, 3-dihydroxy benzonitrile is the key starting material for Desferrithiocin and its analogues. Desferrithiocin (DFT) is an orally effective iron chelator, with a similar high affinity and selectivity for iron to desferrioxamine (DFO), which has been shown clinically 15 to possess antineoplastic activity. Therefore the commercial production for 2, 3-dihydroxy benzonitrile is utmost important.

20

25 [0003] Several conventional processes for the preparation of 2, 3-dihydroxy benzonitrile are available in the literature. Various other procedures in the literature cites the preparation of 2,3-dihydroxy benzonitrile from different starting ma- terials (substituted catechol compounds). A practically more suitable process for the preparation of 2, 3-dihydroxy ben- zonitrile is from the corresponding precursor 2, 3-dialkoxy benzoic acid. A person skilled in the art expects the process 30 to proceed from acid halide, amide, nitrile and dealkylation, wherein the dealkylation step is mandatory to obtain the title compound. [0004] Chemical and Pharmaceutical bulletin vol.58, 11, 2010, 1552-1553 discloses the process for preparation of 2, 3-dihydroxy benzonitrile from 2, 3-dihydroxy benzaldehyde in the presence of formic acid, hydroxylamine hydrochloride and sodium formate. 35 [0005] European Journal of Organic Chemistry 11, 2006, 2513-2516 discloses the process for preparation of 2, 3- dihydroxy benzonitrile from 1, 3-benzodioxole-4-carbaldehyde. Oxidative conversion of aldehydes to nitriles and depro- tection of hydroxy groups done in the presence of 2.2 eq of sodium hexamethyldisilazane in tetrahydrofuran and in highly polar solvent 1,3-Dimethyl-2-imidazolidinone at 185°C in a sealed tube. [0006] Several reviews have been described for deprotection of phenolic ethers. For example, phenolic methyl ethers 40 have deprotected to remove the methyl moiety using hydrogen halide such as hydrogen chloride or hydrogen bromide under highly acidic conditions; highly dark colored products formed in these reactions. In addition the phenolic compounds react further with the halogen compounds used thus setting a major drawback on this route. [0007] Use of Lewis acids such as aluminum chloride or aluminum bromide in dealkylation is well known in the art. U.S. Patent No. 7,253,324 discloses a process of poly O-dealkylation of alkoxy aromatic compounds using a aluminum 45 chloride-N,N-dimethylaniline complex. However the patent restricts towards manufacture of polyphenols such as Res- veratrol, Oxyresveratrol and Gnetol. [0008] A conventional process for producing 2,3-dihydroxy benzonitrile from 2, 3-dimethoxy benzonitrile is disclosed in Journal of Medicinal Chemistry, 2005, Vol. 48, No. 3, 821-831.The disclosed process appears to be the closest prior art involving demethylation in the presence of boron tribromide in dichloromethane. 50 [0009] Boron tribromide is highly moisture sensitive, colorless fuming liquid and decomposes in air with evolution of HBr. It is stored under a dry inert atmosphere and transferred by syringe or through a Teflon tube for the reactions. It reacts violently with protic solvents such as water and alcohols. However the aforementioned process for preparing 2, 3-dihydroxy benzonitrile are less than fully satisfactory in view of hazardous reagents, difficult to handle, expensive, lower temperatures, long reaction times, tedious work up procedures, not liable for scale up process and low reaction 55 yields, thereby limiting their use in commercial scale production. [0010] Despite all prior advances, available methods for synthesizing 2, 3-dihydroxy benzonitrile from 2, 3-dialkoxy benzoic acid which proceed through known intermediates such as the corresponding acid 2, 3-dialkoxy benzoyl chloride, 2, 3-dialkoxy benzamide, 2, 3-dialkoxy benzonitrile remain labor intensive, time consuming and environmentally unfa-

2 EP 2 874 980 B1

vorable. The isolated intermediates are however available in the literature, wherein the isolation of the intermediated are time consuming and practically not suitable for manufacturing scales. Thus, there remains a need for a simple, cost effective, industrially feasible and scalable process for the synthesis of 2, 3-dihydroxy benzonitrile that would avoid the aforementioned difficulties. 5 [0011] The present inventors thus found an alternate approach for preparing 2,3-dihydroxy benzonitrile involving a one-pot synthesis from 2,3-dialkoxy benzoic acid without isolating any intermediates and also involving the use of aluminum salt-amine complex for the dealkylation process.

SUMMARY OF THE INVENTION 10 [0012] The present invention encompasses a one pot process for preparing 2, 3-dihydroxy benzonitrile with high product yield and quality. [0013] In according with one embodiment, the present invention provides a one-pot process for the preparation of 2,3- dihydroxy benzonitrile of Formula I, 15

20

25 comprising the steps of:

a) reacting an acid compound of Formula (II)

30

35

wherein R1 and R2 independently represents C1-4 alkyl group with a suitable halogenating reagent in presence of a suitable solvent to obtain corresponding benzoic acid halide, b) reacting the resulting benzoic acid halide compound with a source of ammonia to obtain corresponding amide of 40 Formula III;

45

50

c) treating the amide compound with a suitable dehydrating reagent to obtain dialkoxy benzonitrile compound of Formula IV, and

55

3 EP 2 874 980 B1

5

10 d) dealkylating the resulting dialkoxy benzonitrile compound with a suitable dealkylating agent;

wherein the steps a) to d) are carried out in a single step without isolating any intermediates. [0014] In according with a second embodiment, the present invention provides a one-pot process for the preparation of 2,3-dihydroxy benzonitrile, comprising the steps of: 15

a) reacting an acid compound of Formula II, wherein R1 and R2 independently represents C1-4 alkyl group with a suitable halogenating reagent in presence of a suitable solvent to obtain corresponding benzoic acid halide, b) quenching the resulting benzoic acid halide compound in to a solution of aqueous ammonia to obtain corresponding amide of Formula III, 20 c) treating the resulting solution of amide compound with a suitable dehydrating reagent to obtain dialkoxy benzonitrile compound of Formula IV, and d) dealkylating the resulting solution of dialkoxy benzonitrile compound with aluminum salt-amine complex to obtain 2,3-dihydroxy benzonitrile of Formula I.

25 [0015] In according with a third embodiment, the present invention provides a process for preparation of 2,3-dihydroxy

benzonitrile of Formula I, comprising: deprotecting dialkoxy benzonitrile compound of Formula IV; wherein R1 and R2 are independently represents H or C1-4 alkyl group, with a suitable dealkylating agent in a suitable organic solvent, wherein the dealkylating agent is aluminum salt-amine complex.

30

35

[0016] In according with a fourth embodiment, the present invention provides a process for preparation of 2,3-dihydroxy 40 benzonitrile of Formula I, comprising: deprotecting dialkoxy benzonitrile compound of Formula IV, wherein R1 and R2 independently represents C1-4 alkyl group, with aluminum salt-amine complex in a suitable organic solvent; wherein the aluminium salt is selected from the group comprising aluminium chloride, aluminium bromide, aluminium iodide and the like and mixtures thereof; and amine is a compound of formula NRaRbRc; in which:

45 Ra, Rb and Rc independently represents a hydrogen, a linear or branched alkyl group, a linear or branched C 2-C6 alkenyl group, a C1-C6 alkanol, a C3-C10 cycloalkyl group, a cycloalkylalkyl group, an aryl group, an aralkyl group or Ra, Rb or Rc may form a cyclic ring with nitrogen.

DETAILED DESCRIPTION OF THE INVENTION 50 [0017] The present invention provides one pot process for the preparation of 2, 3-dihydroxy benzonitrile from 2, 3- dialkoxy benzoic acid suitable for the large scale preparation. [0018] In according with one embodiment, the present invention provides a one-pot process of 2,3-dihydroxy benzoni- trile of Formula I, 55

4 EP 2 874 980 B1

5

10 comprising the steps of:

a) reacting an acid compound of Formula (II)

15

20

wherein R1 and R2 independently represents C1-4 alkyl group with a suitable halogenating reagent in presence of a suitable solvent to obtain corresponding benzoic acid halide, 25 b) reacting the resulting benzoic acid halide compound with a source of ammonia to obtain corresponding amide of Formula III;

30

35

c) treating the amide compound with a suitable dehydrating reagent to obtain dialkoxy benzonitrile compound of Formula IV, and

40

45

d) dealkylating the resulting dialkoxy benzonitrile compound with a suitable dealkylating agent. 50 [0019] In another embodiment, the present invention provides a one-pot process of 2,3-dihydroxy benzonitrile of Formula I, wherein the entire process is carried out in a single step without isolating any process intermediates. [0020] In a preferred embodiment, the starting compound of Formula II is

55

5 EP 2 874 980 B1

5

10 in which R 1 and R 2 independently, represents C 1-4 alkyl group; preferably methyl, ethyl, propyl, isopropyl, ter-butyl; more preferably R1 and R2 are methyl. [0021] The starting material, a compound of Formula II is known in the art and can be prepared by any known method, for example starting compound of Formula II can be synthesized as disclosed in Journal of the American Chemical Society vol. 62,; (1940),1963-1965 or Synthetic Communications; vol. 25, nb. 14, (1995), 2121 -2134 . In an embodiment 15 of the present invention, the halogenation of 2, 3-dialkoxy benzoic acid, preferably 2, 3-dimethoxy benzoic acid of aforementioned step a can be carried out by using a suitable halogenating agent. The halogenating agent is preferably selected from the group consisting of phosphorous trichloride, phosphorus penta chloride, phosphorus oxychloride, thionyl chloride and sulfuryl chloride. More preferably the halogenating agent may be either thionyl chloride or phosphorus oxychloride. 20 [0022] The halogenation of 2, 3-dimethoxy benzoic acid of step a can be carried out in a suitable solvent. The suitable solvent for halogenation is selected from the group consisting of chloroform, dichloromethane, toluene, tetrahydrofuran and dioxane, and preferably dichloromethane. [0023] The halogenation of 2, 3-dimethoxy benzoic acid can be carried out at a temperature of about 20°C to about 50°C; more preferably about 20°C to about 35°C. 25 [0024] Optionally catalytic amount of an amide reagent may be added to the halogenation reaction. The suitable amide reagent is dimethyl formamide. [0025] After completion of the reaction, the reaction mass obtained in step (a) as such may be treated with a source of ammonia to obtain 2, 3-dimethoxy benzamide of Formula III. The source of ammonia in step (b) is selected from the group comprising ammonia gas, ammonium chloride or aqueous ammonia; preferably aqueous ammonia. 30 [0026] In a preferred embodiment, the step a) reaction solution may be quenched into a solution of pre-prepared aqueous ammonia solution at a temperature of about 0°C to about 30°C; more preferably about 10°C to about 15°C to obtain 2, 3-dimethoxy benzamide of Formula III. [0027] After completion of the step b) reaction, the organic and aqueous layers may be separated and the organic layer is concentrated at a temperature of about 45-50°C to obtain Formula III as oily residue, which on further diluted 35 with a suitable water immiscible organic solvent and co-distilling the solvent at a temperature of about 55-60°C until the moisture content of the reaction solution reaches to about 0.5% and proceed further to the step c). The suitable water immiscible organic solvent includes, but is not limited to esters such as methyl acetate, ethyl acetate; aromatic hydro- carbons such as toluene, xylene and the like; ethers such as tetrahydrofuran; and mixtures thereof; preferably toluene. [0028] Step c) of the aforementioned step includes treating the solution of amide compound obtained from step b) 40 with a suitable dehydrating reagent to obtain dimethoxy benzonitrile compound of Formula IV. [0029] The dehydration reagent used is selected from the group consisting of oxyaloyl chloride, oxyaloyl bromide, oxyaloyl iodide,phosphorous trichloride, phosphorous tribromide, phosphorous triiodide, thionyl chloride, thionylbromide, thionyl iodide, phosphorous pentachloride, phosphorus pentoxide, phosphorous oxy chloride, ethyl dichlorophosphate; preferably thionyl chloride, phosphorus oxychloride; more preferably phosphorus oxychloride. 45 [0030] The dehydration of 2, 3-dimethoxy benzamide of step (c) may be carried out at a temperature of about 40°C to about 90°C; more preferably about 75°C to about 85°C. [0031] After completion of the dehydration reaction, the reaction mass obtained in step (c) may be quenched into water and separating the aqueous and organic layers. The resultant organic layer containing product may be subjected to azeotropic distillation at a temperature of about 95-120°C; preferably at about 105-115°C to removing the water from 50 the organic layer and the obtained organic layer containing dimethoxy benzonitrile compound of Formula IV can be further processed directly for the step d) of dealkylation reaction. [0032] In another embodiment, the present invention provides a process for the preparation of 2,3-dihydroxy benzoni- trile of Formula I, comprising deprotecting dialkoxy benzonitrile of compound of Formula IV; wherein R1 and R2 inde- pendently represents C 1-4 alkyl group, preferably methyl, as obtained by the process described above or may be obtained 55 by any known process, as a starting material or as an intermediate with a suitable dealkylating agent in a suitable organic solvent. [0033] In another embodiment, the present invention provides a process for preparation of 2,3-dihydroxy benzonitrile of Formula I, comprising: deprotecting dialkoxy benzonitrile compound of Formula IV; preferably dimethoxy benzonitrile

6 EP 2 874 980 B1

compound of Formula IV obtained by any known process or obtained by the process as described above with a suitable dealkylating agent in a suitable organic solvent, wherein the dealkylating agent is aluminum salt-amine complex. [0034] The aluminium salt include, aluminium chloride, aluminium bromide, aluminium iodide and mixtures thereof; preferably aluminium chloride. 5 [0035] The amine in the fore going process may be a compound of Formula NRaRbRc; in which:

Ra, Rb and Rc independently represents a hydrogen, a linear or branched alkyl group, a linear or branched C 2-C6 alkenyl group, a C1-C6 alkanol, a C3-C10 cycloalkyl group, a cycloalkylalkyl group, an aryl group, an aralkyl group 10 or Ra, Rb or Rc may form a cyclic ring with nitrogen.

[0036] The amine may be in the form of its free amine or its acceptable salt form. [0037] The linear or branched alkyl group includes, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, hexyl, heptyl, octyl, ethylhexyl and the like; the linear or branched C 2-C6 alkenyl group includes, an ethenyl 15 or vinyl, propenyl or allyl, 1-propenyl, n-butenyl, isobutenyl, 3-methylbut-2-enyl, n-pentenyl or hexenyl group; the C 1-C6 alkanol includes, methanol, ethanol, propanol, butanol; the C3-C10 cycloalkyl group includes, cyclopropyl, cyclohexyl; the cycloalkylalkyl group includes, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohep- tylmethyl, cyclopropylethyl or cyclohexylethyl group; the aryl group includes, phenyl, naphthyl, indenyl or anthracenyl; and the aralkyl includes, benzyl, 1-phenylethyl, naphthalenylmethyl or 1-naphthalenylethyl. 20 [0038] Preferably, the amine can be selected from the group consisting of diethylamine, diisopropyl amine, di-n- propylamine, diisobutylamine, diallylamine, allylmethyl amine, diphenylamine, dibenzylamine, trimethylamine, triethyl- amine, tripropylamine, tributylamine, benzylethyl amine, methylbenzyl amine, N,N-dimethylethylamine, N,N-diethylmeth- ylamine, N,N-dimethylbutylamine, dicyclopropylamine, dicyclohexylamine, N-t-butyl cyclohexylamine, N-isobutyl cy- clohexylamine, di(2-ethylhexyl)amine, dicyclohexylmethyl amine, N,N-dimethylaniline, N,N-diethylaniline, N-methyl-N- 25 ethyl aniline, N-methyl-N-isopropyl aniline, 1-N,N-dimethylnaphthalene, 2-N,N-dimethyl naphthalene, 2,6-lutidine and mixtures thereof; more preferably the amine is triethyl amine or dimethylaniline. [0039] The suitable organic solvent for the dealkylation includes esters, ketones, amides, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons and mixtures thereof. The esters include, methyl acetate, ethyl acetate, isopropyl acetate; ketones include, acetone, methyl isobutyl ketone, methyl ethyl ketone; amides include, dimethyl formamide, 30 dimethyl acetamide, N-methyl pyrrolidinone; nitriles include, acetonitrile, propionitrile; ethers include, tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane; halogenated hydrocarbons include, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride; aromatic hydrocarbons include, toluene, xylene. Preferably the solvent is chosen from either chlorinated aliphatic solvents like methylene chloride, ethylene chloride, chloroform, carbon tetrachloride or the aromatic hydrocarbon like toluene, xylenes ; preferably the suitable solvent is 35 toluene. [0040] The entire process for the preparation of 2, 3-dihydroxy benzonitrile form 2, 3-dialkoxy benzoic acid is sche- matically represented as follows:

40

45

50

[0041] Another aspect of the invention, relates to the formation of mono dealkylated benzonitrile impurities in the 55 specified limitations, thus enhancing the purity and yield of the 2, 3-dihydroxy benzonitrile. The mono dealkyated impurities as cited herein are represented as follows:

7 EP 2 874 980 B1

5

[0042] The process of the present invention advantageously provide 2, 3-dihydroxy benzonitrile in relatively high purity, i.e., a purity of greater than or equal to about 99% as measure by HPLC, and more preferably greater than or equal to 10 about 99.5%; and substantially free of impurities A and B. [0043] As used herein, the term "substantially free" refers to 2, 3-dihydroxy benzonitrile having less than 0.1% by HPLC of impurity A or impurity B; particularly less than 0.05% by HPLC of impurity A or impurity B. [0044] The present invention provides 2, 3-dihydroxy benzonitrile, obtained by the above process, as analyzed using high performance liquid chromatography ("HPLC") with the conditions described below: 15 Column Inertsil ODS 3V (150x4.6)mm,5mm Column temperature 30°C

Mobile phase Mobile Phase-A:10mM KH2PO4 pH adjusted to 3.0 with ortho phosphoric acid 20 Mobile Phase-B: Acetonitrile Diluent Water: Acetonitrile(1:1) Flow rate 1.0 ml/min Wavelength 210 nm 25 Injection Volume 10 mL Run time 30 min

30 [0045] The advantages of the present invention thus encompass:

1. A cost effective process, 2. Time saving process as it doesn’t involves any isolation of the intermediates, which would enhance more time consumption during isolations, 35 3. Industrially feasible for scale up. 4. Decreased impurity profile.

[0046] The process of the present invention optionally comprises, a step of collecting 2,3-dihydroxy benzonitrile form the reaction mixture by at least one procedure selected from precipitation, recrystallisation, or by distillation. 40 [0047] The foregoing process thus mentioned above, to prepare 2, 3-dihydroxy benzonitrile is a useful starting material for the preparation of various heterocyclic compounds.

EXAMPLES

45 [0048] The following examples are provided to enable one skilled in art to practice the invention and are merely illustrative of the invention.

EXAMPLE 1:

50 Preparation of 2,3-dihydroxy benzoic acid form 2,3-dimethoxy benzoic acid

[0049] To a stirred solution of 2, 3-dimethoxy benzoic acid (100g; 0.549 mol) in dichloromethane (500 mL) and catalytic amount of DMF (∼2 mL) at a temperature about 30-35°C, thionyl chloride (130.6g ; 1.102 mol) was added and stirred for a period of two hours. Reaction was monitored by TLC for completion of the starting material (NMT-5%). If reaction 55 not completed added thionyl chloride (9.8 g; 0.823 mol). Upon completion of reaction, the reaction mass was quenched in to the -5°C chilled aqueous ammonia (580 mL) solution at a temperature below 15°C under stirring. The reaction mass was stirred at temperature 30-35°C over a period of 30 min. The separated organic fraction was concentrated under atmospheric distillation at below 50°C, charged toluene (100 ml) and co-distilled until the reaction mass moisture

8 EP 2 874 980 B1

content become less than 0.5 %. The obtained benzamide compound was dissolved in toluene (500 mL) at temperature about 30-35°C.To the reaction mass was added POCl 3 (126.3 g; 0.824 mol).The temperature of the reaction mass was raised to 80-85°C and maintained over a period of 1-2 hours for the completion of the reaction (Progress of the reaction was monitored by HPLC until the benzamide NMT 1.0 %). If the reaction was not completed, added second lot of POCl 3 5 (10.1g; 0.06 mol) at 30-35°C. The reaction mass was cooled to a temperature about 30-35°C upon completion of the reaction. The reaction mixture was added to cold water (1000 mL) at 0-5°C.The organic fraction was separated and washed with 8% sodium bicarbonate solution. The organic fraction was separated and azeotropic distilled at 110-115°C (until moisture content NMT 0.2 %), after reaching moisture content to normal limit cooled the reaction mass temperature to 40°C and distilled reaction mass volume becomes ∼3 volumes under vacuum at a temperature 40-50°C.After distillation 10 cooled the reaction mass temperature to 30-35°C. In another RB flask charged toluene (160 ml), triethyl amine (199.7 g; 1.977 mol) at 30-35°C and stirred for 10 min. charged aluminum chloride (52.7 g35; 1.977 mol) in five lots with the gap of 10 min between each lot addition (addition of aluminum chloride may raise the temperature to 45-50°C). The reaction mass temperature was raised to about 70-75°C and added above reaction mass (methoxy compound) for 30 min. maintained the reaction mass at 70-75°C for 8 hr. Progress of the reaction was monitored by HPLC (until the 2,3- 15 dimethoxybenzonitrile content 0.25 % and 3-methoxy-2-hydroxybenzonitrile content 0.2 %). If reaction was not completed added second lot of triethyl amine (27.7 g; 0.27 mol) and aluminum chloride (36.6 g; 0.27 mol).Upon completion of the reaction, the reaction mixture was cooled to 30-35°C and quenched with chilled aqueous HCl (prepared by addition of water (500 ml) and Conc. HCl (500 ml)) at 15°C. Stirred reaction mass at 25-30°C for about 30 min, filtered the obtained solids and separated aqueous and organic layers. Charged MIBK (320 ml) to the solids and charged above aqueous 20 layer, filtered through celite and separated aqueous and organic layers. To the aqueous layer given MIBK (320+160 ml) extractions. To the combined organic layer given 20% sodium chloride solution washing, organic layer was azeotropic distilled at 110°C to remove the water (moisture content NMT 0.2 %).Cooled the reaction mass temperature to 30°C and filtered through 0.45 micron / 1 micron filter. To the filterate charged 1% EDTA (400 ml), stirred for 30 min and filtered through 10 micron cloth. The organic fraction was separated and distilled off to obtain the residue. The residue 25 was treated with dichloromethane (400 ml) and the solid obtained was filtered and dried under vacuum over 6 hr at 60-65°C to obtain the title compound 2, 3-dihydroxy benzonitrile. (56g, yield 75.4%) Purity by HPLC 99.81 %; Impurity A: 0.05% Impurity B: 0.07 % 30 EXAMPLE 2:

Preparation of 2,3-dihydroxy benzoic acid form 2,3-dimethoxy benzoic acid

35 [0050] To a stirred solution of 2,3-dimethoxy benzoic acid (250g; 1.372 mol) in dichloromethane (1250 mL) and catalytic amount of DMF ( ∼5mL) at a temperature about 25-30°C, thionyl chloride (326.5g ; 2.745 mol) was added and stirred for a period of two hours. Upon completion of reaction, the reaction mass was added to the super cooled aqueous ammonia (1450 mL) solution at a temperature about 0-5°C under stirring. The reaction mass was stirred at temperature 0-5°C over a period of 60 min. The separated organic fraction was concentrated under atmospheric distillation at below 50°C, 40 followed by azeotropic distillation with addition of toluene (250mL) to the concentrate. The obtained benzamide compound was dissolved in toluene (1250 mL) at temperature about 25-30°C.To the benzamide compound in toluene as above,

POCl3 (340.2 g; 2.3 mol) was added .The temperature of the reaction mass was raised to 75-80°C and maintained over a period of 1-2 hours for the completion of the reaction. The reaction mass was cooled to a temperature about 25-30°C upon completion of the reaction. The reaction mixture was added to cold water (2500 mL) at 0-5°C. The organic fraction 45 was separated and washed with sodium bicarbonate solution. The organic fraction was separated and distilled under vacuum at a temperature 40-50°C.The benzonitrile compound was dissolved in toluene (475 mL) at room temperature added to a solution of toluene(675 mL) containing dimethyl aniline (498.36 g; 4.11 mol), anhydrous aluminum chloride (549.02 g; 4.11 mol). The reaction mass was raised to a temperature about 110-120°C and maintained over completion about 1-2 hours. Upon completion of the reaction, the reaction mixture was quenched with aqueous HCl at a temperature 50 below 20°C (preferred 0-5°C).To the quenched reaction mass MIBK was added and stirred. The organic fraction was separated and treated with water; brine solution individually .The organic fraction was separated and distilled off to obtain the residue. The residue was treated with dichloromethane and the solid obtained was filtered and dried under vacuum over 6 hr period at 55-60°C to obtain the title compound 2, 3-dihydroxy benzonitrile. (127g, over all yield ∼ 70 %) 55 Purity by HPLC 99.68 %;

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Claims

1. A one-pot process for the preparation of 2,3-dihydroxy benzonitrile of Formula I,

5

10

comprising the steps of: 15 a) reacting an acid compound of Formula (II)

20

25

wherein R1 and R 2 independently represents a C 1-4 alkyl group with a suitable halogenating reagent in presence of a suitable solvent to obtain corresponding benzoic acid halide, b) reacting the resulting benzoic acid halide compound with a source of ammonia to obtain corresponding amide 30 of Formula III;

35

40 c) treating the amide compound with a suitable dehydrating reagent to obtain dialkoxy benzonitrile compound of Formula IV, and

45

50

d) dealkylating the resulting dialkoxy benzonitrile compound with a suitable dealkylating agent in a suitable organic solvent; 55 wherein the steps a) to d) are carried out in a single step without isolating any intermediates.

2. The process of claim 1, wherein the C 1-4 alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl,

10 EP 2 874 980 B1

ter-butyl.

3. The process of claim 1, wherein the halogenating reagent is selected from the group consisting of phosphorous trichloride, phosphorus penta chloride, phosphorus oxychloride, thionyl chloride and sulfuryl chloride. 5 4. The process of claim 1, wherein the suitable solvent for halogenation is selected from the group consisting of chloroform, dichloromethane, toluene, tetrahydrofuran and 1,4-dioxane.

5. The process of claim 1, wherein the source of ammonia is selected from the group comprising ammonia gas, 10 ammonium chloride or aqueous ammonia.

6. The process of claim 1, wherein the dehydrating reagent is selected from the group consisting of oxyaloyl chloride, oxyaloyl bromide, oxyaloyl iodide, phosphorous trichloride, phosphorous tribromide, phosphorous triiodide, thionyl chloride, thionyl bromide, thionyl iodide, phosphorous pentachloride, phosphorus pentoxide, phosphorous oxy chlo- 15 ride and ethyl dichlorophosphate.

7. The process of claim 1, wherein the dealkylating agent is aluminium salt-amine complex.

8. A process for preparation of 2,3-dihydroxy benzonitrile of Formula I, 20

25

30 comprising: deprotecting dialkoxy benzonitrile compound of Formula IV; wherein R 1 and R 2 independently represents a C1-4 alkyl group, with aluminum salt-amine complex in a suitable organic solvent.

35

40

9. The process of claim 8, wherein the C 1-4 alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, ter-butyl.

45 10. The process of claim 7 or 8, wherein the aluminium salt is selected from the group consisting of aluminium chloride, aluminium bromide and aluminium iodide.

11. The process of claim 7 or 8, wherein the amine is selected from a compound of formula NRaRbRc; in which: 50 Ra, Rb and Rc independently represents a hydrogen, a linear or branched alkyl group, a linear or branched

C2-C6 alkenyl group, a C1-C6 alkanol, a C3-C10 cycloalkyl group, a cycloalkylalkyl group, an aryl group, an aralkyl group or Ra, Rb or Rc may form a cyclic ring with nitrogen.

55 12. The process of claim 7 or 8, wherein the amine is selected from the group consisting of diethylamine, diisopropyl amine, di-n-propylamine, diisobutylamine, diallylamine, allylmethyl amine, diphenylamine, dibenzylamine, trimeth- ylamine, triethylamine, tripropylamine, tributylamine, benzylethyl amine, methylbenzyl amine, N,N-dimethylethyl- amine, N,N-diethylmethylamine, N,N-dimethylbutylamine, dicyclopropylamine, dicyclohexylamine, N-t-butyl cy-

11 EP 2 874 980 B1

clohexylamine, N-isobutyl cyclohexylamine, di(2-ethylhexyl)amine, dicyclohexylmethyl amine, N,N-dimethylaniline, N,N-diethylaniline, N-methyl-N-ethyl aniline, N-methyl-N-isopropyl aniline, 1-N,N-dimethylnaphthalene, 2-N,N-dime- thyl naphthalene and 2,6-lutidine.

5 13. The process of claim 7 or 8, wherein the aluminium salt-amine complex is aluminium chloride- N,N-dimethylaniline complex or aluminium chloride- triethylamine complex.

14. The process of claim 7 or 8, wherein the suitable organic solvent for dealkylation is selected from the group consisting of esters, ketones, amides, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons and mixtures thereof. 10 15. A process for the preparation of a desazadesferrithiocin analogue comprising the steps of:

i) preparing a 2,3-dihydroxy benzonitrile according to the process as defined in any one of the preceding claims, and 15 ii) converting the 2,3-dihydroxy benzonitrile obtained in step (i) into the desazadesferrithiocin analogue.

Patentansprüche

20 1. Eintopfverfahren für die Herstellung von 2,3-Dihydroxybenzonitril der Formel I

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umfassend die Schritte:

35 a) Reaktion der Säure der Formel (II)

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wobei R1 und R 2 unabhängig voneinander C 1-4-Alkyl darstellen, mit einem geeigneten Halogenierungsreagenz in Gegenwart eines geeigneten Lösungsmittel, um das entsprechende Benzoesäurehalogenid zu erhalten, 50 b) Reaktion des resultierenden Benzoesäurehalogenids mit einer Aminquelle, um das entsprechende Amid der Formel III zu erhalten;

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c) Umsetzung der Amidverbindung mit einem geeigneten Dehydratisierungsreagenz, um eine Dialkoxybenzo- nitrilverbindung der Formel IV zu erhalten, und 15

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d) Dealkylierung der resultierenden Dialkoxybenzonitrilverbindung mit einem geeigneten Dealkylierungsrea- genz in einem geeigneten organischen Lösungsmittel; 30 wobei die Schritte a) bis d) in einem einzigen Schritt, ohne Isolierung der Intermediate, durchgeführt werden.

2. Verfahren gemäß Anspruch 1, wobei die C 1-4-Alkylgruppe aus Methyl, Ethyl, Propyl, Isopropyl, tert-Butyl ausgewählt ist. 35 3. Verfahren gemäß Anspruch 1, wobei das Halogenierungsreagenz aus Phosphortrichlorid, Phosphorpentachlorid, Phosphoroxychlorid, Thionylchlorid und Sulfurylchlorid ausgewählt ist.

4. Verfahren gemäß Anspruch 1, wobei das für die Halogenierung geeignete Lösungsmittel aus Chloroform, Dichlor- 40 methan, Toluol, Tetrahydrofuran und 1,4-Dioxan ausgewählt ist.

5. Verfahren gemäß Anspruch 1, wobei die Aminquelle aus gasförmigen Ammoniak, Ammoniumchlorid oder einer wässrigen Ammoniaklösung ausgewählt ist.

45 6. Verfahren gemäß Anspruch 1, wobei das Dehydratisierungsreagenz aus Oxalylchlorid, Oxalylbromid, Oxalyliodid, Phosphortrichlorid, Posphortribromid, Phosphortriiodid, Thionylchlorid, Thionylbromid, Thionyliodid, Phosphorpen- tachlorid, Phosphorpentoxid, Phosphoroxychlorid und Ethyldichlorphosphat ausgewählt ist.

7. Verfahren gemäß Anspruch 1, wobei das Dealkylierungsreagenz ein Aluminiumsalz/Aminkomplex ist. 50 8. Verfahren zur Herstellung von 2,3-Dihydroxybenzonitril der Formel I

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umfassend: Entschützen der Dialkoxybenzonitrilverbindung der Formel IV; wobei R1 und R2 unabhängig vonein- ander C 1-4-Alkyl darstellen, mit einem Aluminiumsalz/Aminkomplex in einem geeigneten organischen Lösungsmittel. 15

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9. Verfahren gemäß Anspruch 8, wobei die C 1-4-Alkylgruppe aus Methyl, Ethyl, Propyl, Isopropyl, tert-Butyl ausgewählt ist. 30 10. Verfahren gemäß Anspruch 7 oder 8, wobei das Aluminiumsalz aus Aluminiumchlorid, Aluminiumbromid und Alu- miniumiodid ausgewählt ist.

11. Verfahren gemäß Anspruch 7 oder 8, wobei das Amin eine Verbindung der Formel NRaRbRc ist, 35 wobei:

Ra, Rb und Rc unabhängig voneinander Wasserstoff, eine lineare oder verzweigte Alkylgruppe, eine lineare

oder verzweigte C 2-6-Alkenylgruppe, ein C 1-6-Alkanol, eine C 3-10-Cycloalkylgruppe, eine Cycloalkylalkylgruppe, eine Arylgruppe, eine Aralkylgruppe darstellen, oder Ra, Rb oder Rc einen cyclischen Ring mit dem Stickstoff- 40 atom bilden.

12. Verfahren gemäß Anspruch 7 oder 8, wobei das Amin ausgewählt ist aus Diethylamin, Diisopropylamin, Di-n- propylamin, Diisobutylamin,Diallylamin, Allylmethylamin, Diphenylamin, Dibenzylamin,Trimethylamin, Triethylamin, Tripropylamin, Tributylamin, Benzylethylamin, Methylbenzylamin, N,N-Dimethylethylamin, N,N-Diethylmethylamin, 45 N,N-Dimethylbutylamin, Dicyclopropylamin, Dicyclohexylamin, N-t-Butylcyclohexylamin, N-Isobutylcyclohexylamin, Di(2-ethylhexyl)amin, Dicyclohexylmethylamin, N,N-Dimethylanilin, N,N-Diethylanilin, N-Methyl-N-ethylanilin, N- Methyl-N-isopropylanilin, 1-N,N-Dimethylnaphthalen, 2-N,N-Dimethylnaphthalen und 2,6-Lutidin.

13. Verfahren gemäß Anspruch 7 oder 8, wobei der Aluminiumsalz/Aminkomplex ein Aluminiumchlorid/N,N-Dimethyla- 50 nilinkomplex oder ein Aluminiumchlorid/ Triethylaminkomplex ist.

14. Verfahren gemäß Anspruch 7 oder 8, wobei das geeignete organische Lösungsmittel für die Dealkylierung aus Estern, Ketonen, Amiden, Nitrilen, Ethern, halogenierten Kohlenwasserstoffen, aromatischen Kohlenwasserstoffen und Gemischen davon ausgewählt ist. 55 15. Verfahren zur Herstellung eines Analogons von Desazadesferrithiocin umfassend die Schritte:

14 EP 2 874 980 B1

i) Herstellen von 2,3-Dihydroxybenzonitril gemäß dem Verfahren wie in einem der vorstehenden Ansprüche definiert und ii) Überführen des in Schritt (i) erhaltenen 2,3-Dihydroxybenzonitrils in das Analogon von Desazadesferrithiocin.

5 Revendications

1. Procédé monotope pour la préparation de 2,3-dihydroxybenzonitrile de Formule I,

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20 comprenant les étapes de :

a) réaction d’un composé d’acide de Formule (II)

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35 danslaquelle R1et R2représentent indépendammentun groupe alkyle en C1à C4 avec un réactif d’halogénation adéquat en présence d’un solvant adéquat pour obtenir l’halogénure d’acide benzoïque correspondant, b) la réaction du composé d’halogénure d’acide benzoïque résultant avec une source d’ammoniaque pour obtenir l’amide correspondant de Formule III ; 40

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c) le traitement du composé d’amide avec un réactif de déshydratation adéquat pour obtenir le composé de dialcoxybenzonitrile de Formule IV, et

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d) la désalkylation du composé de dialcoxybenzonitrile résultant avec un agent de désalkylation adéquat dans un solvant organique adéquat ; 15 dans lequel les étapes a) à d) sont réalisées en une seule étape sans isoler aucun intermédiaire.

2. Procédé selon la revendication 1, dans lequel l’alkyle en C1 à C4 est choisi dans le groupe constitué du méthyle, de l’éthyle, du propyle, de l’isopropyle, du ter-butyle. 20 3. Procédé selon la revendication 1, dans lequel le réactif d’halogénation est choisi dans le groupe constitué du trichlorure de phosphore, du pentachlorure de phosphore, de l’oxychlorure de phosphore, du chlorure de thionyle et du chlorure de sulfuryle.

25 4. Procédé selon la revendication 1, dans lequel le solvant d’halogénation adéquat est choisi dans le groupe constitué du chloroforme, du dichlorométhane, du toluène, du tétrahydrofuranne et du 1,4-dioxane.

5. Procédé selon la revendication 1, dans lequel la source d’ammoniaque est choisie dans le groupe comprenant un gaz d’ammoniac, du chlorure d’ammonium ou de l’ammoniaque aqueuse. 30 6. Procédé selon la revendication 1, dans lequel le réactif de déshydratation est choisi dans le groupe constitué du chlorure d’oxyaloyle, du bromure d’oxyaloyle, de l’iodure d’oxyaloyle, du trichlorure de phosphore, du tribromure de phosphore, du triiodure de phosphore, du chlorure de thionyle, du bromure de thionyle, de l’iodure de thionyle, du pentachlorure de phosphore, du pentoxyde de phosphore, de l’oxychlorure de phosphore et du dichlorophosphate 35 d’éthyle.

7. Procédé selon la revendication 1, dans lequel l’agent de désalkylation est un complexe sel d’aluminium-amine.

8. Procédé de préparation de 2,3-dihydroxybenzonitrile de Formule I, 40

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comprenant : la déprotection du composé de dialcoxybenzonitrile de Formule IV ; formule dans laquelle R1 et R2 représentent indépendamment un groupe alkyle en C1 à C4, avec un complexe sel d’aluminium-amine dans un solvant organique adéquat. 55

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9. Procédé selon la revendication 8, dans lequel l’alkyle en C1 à C4 est choisi dans le groupe constitué du méthyle, de l’éthyle, du propyle, de l’isopropyle, du ter-butyle.

15 10. Procédé selon la revendication 7 ou 8, dans lequel le sel d’aluminium est choisi dans le groupe constitué du chlorure d’aluminium, du bromure d’aluminium et de l’iodure d’aluminium.

11. Procédé selon la revendication 7 ou 8, dans lequel l’amine est choisie parmi un composé de Formule NRaRbRc ; dans laquelle : Ra, Rb et Rc représentent indépendamment un atome d’hydrogène, un groupe alkyle linéaire ou 20 ramifié, un groupe alcényle en C2 à C6, linéaire ou ramifié, un alcanol en C1 à C6, un groupe cycloalkyle en C3 à C10, un groupe cycloalkylalkyle, un groupe aryle, un groupe aralkyle ou Ra, Rb ou Rc peuvent former un noyau cyclique avec de l’azote.

12. Procédé selon la revendication 7 ou 8, dans lequel l’amine est choisie dans le groupe constitué de la diéthylamine, 25 de la diisopropylamine, de la di-n-propylamine, de la diisobutylamine, de la diallylamine, de l’allylméthylamine, de la diphénylamine, de la dibenzylamine, de la triméthylamine, de la triéthylamine, de la tripropylamine, de la tributy- lamine, de la benzyléthylamine, de la méthyl-benzylamine, de la N,N-diméthyléthylamine, de la N,N-diéthylméthy- lamine, de la N,N-diméthylbutylamine, de la dicyclopropylamine, de la dicyclohexylamine, de la N-t-butylcyclohexy- lamine, de la N-isobutylcyclohexylamine, de la di(2-éthyl-hexyl)amine, de la dicyclohexylméthylamine, de la N,N- 30 diméthylaniline, de la N,N-diéthylaniline, de la N-méthyl-N-éthylaniline, de la N-méthyl-N-isopropyl-aniline, du 1- N,N-diméthylnaphtalène, du 2-N,N-diméthylnaphtalène et de la 2,6-lutidine.

13. Procédé selon la revendication 7 ou 8, dans lequel le complexe sel d’aluminium-amine est un complexe chlorure d’aluminium-N,N-diméthylaniline ou un complexe chlorure d’aluminium-triéthylamine. 35 14. Procédé selon la revendication 7 ou 8, dans lequel le solvant organique adéquat pour la désalkylation est choisi dans le groupe constitué des esters, des cétones, des amides, des nitriles, des éthers, des hydrocarbures halogénés, des hydrocarbures aromatiques et de leurs mélanges.

40 15. Procédé pour la préparation d’un analogue de la désazadesferrithiocine comprenant les étapes de :

i) préparation d’un 2,3-dihydroxybenzonitrile selon le procédé tel que défini dans l’une quelconque des reven- dications précédentes, et ii) conversion du 2,3-dihydroxybenzonitrile obtenu à l’étape (i) en l’analogue de la désazadesferrithiocine. 45

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17 EP 2 874 980 B1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• US 7253324 B [0007]

Non-patent literature cited in the description

• Chemical and Pharmaceutical bulletin, 2010, vol. 58 • Journal of the American Chemical Society, 1940, vol. (11), 1552-1553 [0004] 62, 1963-1965 [0021] • European Journal of Organic Chemistry, 2006, vol. • Synthetic Communications, 1995, vol. 25 (14), 11, 2513-2516 [0005] 2121-2134 [0021] • Journal of Medicinal Chemistry, 2005, vol. 48 (3), 821-831 [0008]

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