WO2018207120A1 - A process for the preparation of 4-fluoro-2-methoxy-5-nitroaniline - Google Patents

A process for the preparation of 4-fluoro-2-methoxy-5-nitroaniline Download PDF

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WO2018207120A1
WO2018207120A1 PCT/IB2018/053246 IB2018053246W WO2018207120A1 WO 2018207120 A1 WO2018207120 A1 WO 2018207120A1 IB 2018053246 W IB2018053246 W IB 2018053246W WO 2018207120 A1 WO2018207120 A1 WO 2018207120A1
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acid
fluoro
methoxy
sodium
formula
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PCT/IB2018/053246
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French (fr)
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Takshinamoorthy CHANDIRAN
Sivakumaran Meenakshisunderam
Mundla SREENIVASA REDDY
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Aurobindo Pharma Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a process for the preparation of 4-fiuoro-2- methoxy-5-nitroaniline (I) or salts thereof.
  • the compound of Formula I is a key starting material in the preparation of EGFR tyrosine kinase inhibitor, Osimertinib or salt thereof, of Formula II.
  • Osimertinib (II) is chemically known as N-(2- ⁇ 2-dimethylaminoethyl methylamino ⁇ -4-methoxy-5 - ⁇ [4-( 1 -methylindol-3-yl)pyrimidin-2-yl]amino ⁇ phenyl)prop-2-enamide mesylate salt.
  • Osimertinib is a kinase inhibitor indicated for the treatment of patients with metastatic epidermal growth factor receptor (EGFR).
  • EGFR metastatic epidermal growth factor receptor
  • 4-FluoiO-2-methoxy-5-nitroaniline (I) is a key starting material used in the preparation of Osimertinib of Formula II.
  • Osimertimb mesylate is being marketed in the US under the brand name Tagrisso ® .
  • Osimertinib (II) is first reported in the US patent US 8,946,235. US '235, discloses a process for the preparation of Compound of Formula I by nitration of 4-fluoro-2-methoxyaniline (III) using KNO 3 /H2SO4 mixture.
  • US 8,426,427 disclose a process for the preparation of Compound of Formula I by nitration of 4-fluoro-2-methoxyaniline (III) using guanidine nitrate/H 2 S0 4 .
  • Scheme-II CN 104761544 discloses a process for the preparation of Compound of Formula I by reacting l,5-difluoro-2,4-dinitrobenzene (IV) with methanol in presence of 2C0 3 to obtain l-fluoro-5-methoxy-2,4-dinitrobenzene (V) followed by treating with sodium dithionite.
  • the process is as shown in Scheme-Ill below:
  • the present invention is directed towards a process for the preparation of 4- fluoro-2-methoxy-5-nitroaniline (I) or salts thereof, wherein, 4-fluoro-2-methoxy aniline (III) is protected to obtain N-protected-(4-fluoro-2-methoxy)aniline (VI), which is nitrated to obtain N-protected-(4-fluoro-2-methoxy-5-nitro)aniline (VII) and finally deprotected to obtain 4-fluoro-2-methoxy-5-nitroaniline (I) or salt thereof.
  • the main objective of the present invention is to provide a simple, industrially feasible and cost effective process for the preparation of 4-fluoro-2-methoxy-5- nitroaniline of formula (I) or pharmaceutically acceptable salts thereof with high purity and good yield on commercial scale.
  • the main embodiment of the present invention is to provide a process for the preparation of 4-fluoro-2-methoxy-5-nitroaniline (I) or pharmaceutically acceptable salts thereof;
  • the present invention is related to a process for the preparation of 4-fluoro-2- methoxy-5-nitroaniline (I) or pharmaceutically acceptable salts thereof.
  • the process comprises, 4-fluoro-2-methoxy aniline (III) is protected to obtain N- protected-(4-fluoro-2-methoxyphenyl)aniline (VI) .
  • the N-protecting group comprises acetyl (Ac), carbobenzyloxy (Cbz or Z) group, -methoxybenzyl carbonyl (Moz or MeOZ) group, Allyl carbamate (Alloc) group, benzoyl (Bz) group, benzyl (Bn) group, carbamate group, 2,2,2-trichloroethyl carbamate (Troc) group, />-methoxybenzyl (PMB) group, 3,4- dimethoxybenzyl (DMPM) group, / methoxyphenyl (PMP) group, tosyl (Ts) group, 2-trimethylsilylethyl carbamate (Teoc) group or other sulfonamides (Nosyl & Nps) groups and the like.
  • the above reaction is carried out using corresponding carbonyl compounds such as acetic anhydride, acetyl chloride, BnOCOCl or (BnOCO) 2 0, allyl chloroformate or (Alloc) 2 0, benzoyl chloride, benzyl halide (BnCl or BnBr), carbamic acid, 2,2,2-trichloroethyloxy carbonyl chloride, PMB trichloroacetimidate, 2,4-dimethoxybenzaldehyde, p-methoxybenzyl chloride, tosyl chloride, 2-trimethylsilylethyloxy carbonyl chloride (Teo-Cl) or Teoc-N 3 .
  • carbonyl compounds such as acetic anhydride, acetyl chloride, BnOCOCl or (BnOCO) 2 0, allyl chloroformate or (Alloc) 2 0, benzoyl chloride, benzyl halide (BnC
  • the n-protection may be carried out in presence of an acid or a base.
  • the acid comprises an organic acid selected from formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, oxalic acid, lactic acid, malic acid, citric acid, benzoic acid, carbonic acid, methane sulfonic acid and p- toluene sulfonic acid or a inorganic acid selected from hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, boric acid, hydrofluoric acid, hydrobromic acid, perchloric acid and hydroiodic acid or mixtures thereof.
  • organic acid selected from formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, oxalic acid, lactic acid, malic acid, citric acid, benzoic acid, carbonic acid, methane sulfonic acid and p- toluene sulfonic acid or a inorganic acid selected from hydrochloric acid, n
  • the base comprises an organic base selected from pyridine, triethylamine, methyl amine, imidazole, benzimidazole, histidine, phosphazene and 2,6-Lutidine or a inorganic base selected from potassium methoxide, potassium ethoxide, potassium tertiary butoxide, sodium methoxide, sodium ethoxide, sodium tertiary butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate, potassium acetate or ammonia, ammonium hydroxide, ammonium carbonate or mixtures thereof.
  • organic base selected from pyridine, triethylamine, methyl amine, imidazole, benzimidazole, histidine, phosphazene and 2,6-Lutidine
  • a inorganic base selected from potassium methoxide, potassium ethoxide, potassium tertiary
  • the above reaction is carried out in the presence/absence of a solvent.
  • the solvent comprises water, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, toluene, benzene, o-xylene, m-xylene, p-xylene, acetone, acetonitrile, ethyl acetate, methylene chloride, dioxane, DMF, THF or mixture thereof.
  • the compound (VI) is isolated as a solid or as such used in next step.
  • Compound (VI) is subjected to purification either by column chromatography or by crystallization.
  • Still another embodiment of the present invention is N-protected-(4-fluoro-2- methoxyphenyl)aniline (VI) undergoes nitration in presence of nitrating agent to obtain N-protected-(4-fluoro-2-methoxy-5-nitro)aniline (VII).
  • the nitrating agent used in the above reaction comprises nitric acid, sodium nitrate, potassium nitrate and/ or acid.
  • the acid comprises hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, boric acid, hydrofluoric acid, hydrobromic acid, perchloric acid and hydroiodic acid or mixtures thereof.
  • the above nitration is carried out in presence/absence of a solvent.
  • the solvent comprises of benzene, toluene, xylene, chlorobenzene, chlorotoluene, chloroform, carbon tetrachloride and water or mixtures thereof.
  • the compound (VII) is isolated as a solid or as such used in next step.
  • Compound (VII) is subjected to purification either by column chromatography or by crystallization.
  • Yet another embodiment of the present invention is de-protection of N-protected- (4-fluoro-2-methoxy-5-nitro)aniline (VII) to obtain 4-fluoro-2-methoxy-5- nitroaniline (I) or pharmaceutically acceptable salts thereof.
  • the above reaction is carried out in presence of an acid, a base or a reducing agent.
  • the acid used in the above reaction comprises hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, boric acid, hydrofluoric acid, hydrobromic acid, perchloric acid and hydroiodic acid, Periodic acid and trichloroisocyanuric acid, trifluoro acetic acid or mixtures thereof.
  • the base used in the above reaction comprises ammonia, methylamine, morpholine, diisopropylethyl amine, ammonium cerium(IV) nitrate (CAN), sodium in liquid ammonia or sodium naphthalenide, samarium iodide, tributyltin hydride or mixtures thereof.
  • the reducing agent used in the above reaction comprises palladium-on-carbon (Pd/C), Tetrakis(triphenylphosphine)palladium(0), nickel nanoparticles immobilized on hierarchical zeolite, platinum(IV) oxide, iron in acidic media such as acetic acid, formic acid, hydrochloric acid, hydrobromic acid and the like; sodium hydrosulfite, sodium sulfide, tin(II) chloride, titanium(III) chloride, zinc, rhodium, ruthenium and nickel catalysts such as raney nickel or urushibara nickel.
  • the above reaction is carried out in the presence/absence of a solvent.
  • the solvent comprises an alcohol selected from Ci-Cio straight or branched chain alcohol such as methanol, ethanol, isopropyl alcohol, l-butanol,2-butanol, 2-methyl-2- propanol, 1-pentanol, 2-pentanol, 2,2-dimethyl-l-propanol, 2,2,2-trimethyl ethanol, 1-decanol, benzyl alcohol; hydrocarbon solvent selected from the group toluene, benzene, o-xylene, m-xylene, p-xylene, water, acetone, acetonitrile, ethyl acetate; methylene chloride, DMF, dioxane, THF or mixture thereof.
  • Ci-Cio straight or branched chain alcohol such as methanol, ethanol, isopropyl alcohol, l-butanol,2-butanol, 2-methyl-2- propanol, 1-pentanol, 2-pentanol,
  • the compound (I) is isolated as a solid or as such used in next step.
  • Compound (I) is subjected to purification either by column chromatography or by crystallization.
  • Yet another embodiment of the present invention is 4-fiuoro-2-methoxy-5- nitroaniline (I) or pharmaceutically acceptable salts thereof as produced by the process described above, and is converted to Osimertinib or pharmaceutically acceptable salts thereof (II) by known process.
  • 4-fiuoro-2-methoxy aniline (III) used in the present invention is prepared by reacting 2,4-difluoro nitrobenzene (VIII) with methanol in presence of a base to produce 4-fluoro-2-methoxy nitrobenzene (IX), which is reduced to give 4-fluoro-2-methoxy aniline (III).
  • the base used in above reaction comprises alkali metal alkoxide selected from potassium methoxide, potassium ethoxide, potassium tertiary butoxide, sodium methoxide, sodium ethoxide, sodium tertiary butoxide, alkali metal hydroxide selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, alkali metal carbonate selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, alkali metal acetate selected from sodium acetate, potassium acetate or ammonia, ammonium hydroxide, ammonium carbonate or mixtures thereof.
  • alkali metal alkoxide selected from potassium methoxide, potassium ethoxide, potassium tertiary butoxide, sodium methoxide, sodium ethoxide, sodium tertiary butoxide
  • alkali metal hydroxide selected from sodium hydroxide, potassium hydroxide, lithium hydroxide
  • alkali metal carbonate selected from sodium carbonate, potassium carbonate, sodium
  • the above reaction is carried out in the presence/absence of a solvent.
  • the solvent comprises hydrocarbon selected from toluene, benzene, o-xylene, m-xylene, p- xylene, water, methanol, ethanol, propanol, isopropanol, butanol or isobutanol, acetone, acetonitrile, ethyl acetate, methylene chloride, Dimethyl formamide (DMF), Tetrahydrofuran (THF) or mixture thereof.
  • DMF Dimethyl formamide
  • THF Tetrahydrofuran
  • the compound (IX) is isolated as a solid or as such used in next step.
  • Compound (IX) is subjected to purification either by column chromatography or by crystallization.
  • the above reduction is carried out in the presence/absence of a solvent.
  • the solvent selected from Ci-Cio straight or branched chain alcohol such as methanol, ethanol, isopropyl alcohol, l-butanol,2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 2,2-dimethyl-l -propanol, 2,2,2-trimethyl ethanol, 1-decanol, benzyl alcohol; toluene, benzene, o-xylene, m-xylene, p-xylene, water, acetone, acetonitrile, ethyl acetate, methylene chloride, dioxane, DMF, THF or mixture thereof.
  • the following example(s) illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.
  • Example-l illustrate the nature of the invention and are provided for il
  • Step-A process for the preparation of 4-fluoro-2-methoxy-l-nitrobenzene: Toluene (500 ml) was added into clean and dry round bottom flask, then 2,4- difluoro-1 -nitrobenzene (500 gms) was added. The reaction mass was cooled to 0°C then methanol (100 ml) was slowly added to reaction mass at 0°C. To the reaction mass potassium tert-butoxide (PTB) (353 gms) was added in lots (10 lots) at 0°C. The reaction mass was stirred at 0°C for 15-30 minutes, then temperature raised to 20°C and the reaction mass was stirred at 20°C for 4 hrs.
  • PTB tert-butoxide
  • the reaction mass was decomposed in water (1500 ml). The contents were stirred for 10-15 minutes followed by toluene was added to the reaction mass. The layers were separated, and the aqueous layer was extracted with toluene followed by separated the organic layer. Total organic layer was washed with water (1000 ml). The organic layer was then washed with brine solution (NaCl (50 gms) + water (500 ml)) and dried over sodium sulphate. The solvent was distilled out under vacuum. Petroleum ether (1000 ml) was added to the residue and the contents were cooled to below 10°C then stirred for 30 minutes. The solid was filtered off and washed with petroleum ether (200 ml). The solid was dried at 50-60°C for 3-5 hrs (Yield - 470 gms; 87.38%).
  • Step-C Process for the preparation of N-(4-fluoro-2-methoxy phenyl) acetamide:
  • acetic acid 950 ml
  • 4-fluoro-2-methoxyaniline 380 gms
  • the reaction mass was stirred at 25-30°C for 10-15 minutes.
  • Acetic anhydride (439 gms) was added slowly to the reaction mass at 25- 35°C in 1.0-2.0 hrs.
  • the reaction mass was heated to 90°C and stirred at same temperature for 3.0-5.0 hrs.
  • the reaction mass was decomposed into water (1000 ml) and stirred at 25-30°C for 1.0-2.0 hrs.
  • the solid was filtered and washed with water (300 ml).
  • the reaction mass was extracted with ethyl acetate (2000 ml).
  • Step D process for the preparation of N-(4-fluoro-2-methoxy-5-nitrophenyl) acetamide:
  • Step E Process for the preparation of 4-fluoro-2-methoxy-5-nitroaniline:

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Abstract

The present invention is directed towards a process for the preparation of 4- fluoro-2-methoxy-5-nitroaniline (I) or salts thereof, wherein, 4-fluoro-2-methoxy aniline (III) is protected to obtain N-protected-(4-fiuoro-2-methoxy)aniline (VI), which is nitrated to obtain N-protected-(4-fluoro-2-methoxy-5-nitro)aniline (VII) and finally deprotected to obtain 4-fluoro-2-methoxy-5-nitroaniline (I) or salt thereof.

Description

A PROCESS FOR THE PREPARATION OF 4-FLUORO-2-METHOXY-5- NITRO ANILINE
FIELD OF INVENTION
The present invention relates to a process for the preparation of 4-fiuoro-2- methoxy-5-nitroaniline (I) or salts thereof.
Formula I
Figure imgf000002_0001
The compound of Formula I is a key starting material in the preparation of EGFR tyrosine kinase inhibitor, Osimertinib or salt thereof, of Formula II.
Formula II
Figure imgf000002_0002
BACKGROUND OF THE INVENTION
Osimertinib (II) is chemically known as N-(2-{2-dimethylaminoethyl methylamino } -4-methoxy-5 - { [4-( 1 -methylindol-3-yl)pyrimidin-2-yl]amino } phenyl)prop-2-enamide mesylate salt. Osimertinib is a kinase inhibitor indicated for the treatment of patients with metastatic epidermal growth factor receptor (EGFR). 4-FluoiO-2-methoxy-5-nitroaniline (I) is a key starting material used in the preparation of Osimertinib of Formula II. Osimertimb mesylate is being marketed in the US under the brand name Tagrisso®. Osimertinib (II) is first reported in the US patent US 8,946,235. US '235, discloses a process for the preparation of Compound of Formula I by nitration of 4-fluoro-2-methoxyaniline (III) using KNO3/H2SO4 mixture.
The process is as shown in scheme-I below:
Figure imgf000003_0001
(III) (I)
Scheme-I
US 8,426,427 disclose a process for the preparation of Compound of Formula I by nitration of 4-fluoro-2-methoxyaniline (III) using guanidine nitrate/H2S04.
The process is as shown in Scheme-II below:
Figure imgf000003_0002
(III) (I)
Scheme-II CN 104761544 discloses a process for the preparation of Compound of Formula I by reacting l,5-difluoro-2,4-dinitrobenzene (IV) with methanol in presence of 2C03 to obtain l-fluoro-5-methoxy-2,4-dinitrobenzene (V) followed by treating with sodium dithionite. The process is as shown in Scheme-Ill below:
Figure imgf000004_0001
Scheme-Ill
The major disadvantage with the prior-art is the yields are low and isolation of pure compound was problematic.
However, there is always a need for an alternative process, which for example, involves use of reagents that are less expensive and/or easier to handle, consume smaller amounts of reagents, provide a higher yield of product, have smaller and/or more eco-friendly waste products, and/or provide a product of higher purity.
Hence, there is a need to develop cost effective and commercially viable process for the preparation of 4-fluoro-2-methoxy-5-nitroaniline (I) or salts thereof.
The present invention is directed towards a process for the preparation of 4- fluoro-2-methoxy-5-nitroaniline (I) or salts thereof, wherein, 4-fluoro-2-methoxy aniline (III) is protected to obtain N-protected-(4-fluoro-2-methoxy)aniline (VI), which is nitrated to obtain N-protected-(4-fluoro-2-methoxy-5-nitro)aniline (VII) and finally deprotected to obtain 4-fluoro-2-methoxy-5-nitroaniline (I) or salt thereof.
OBJECTIVE OF INVENTION The main objective of the present invention is to provide a simple, industrially feasible and cost effective process for the preparation of 4-fluoro-2-methoxy-5- nitroaniline of formula (I) or pharmaceutically acceptable salts thereof with high purity and good yield on commercial scale. SUMMARY OF THE INVENTION
The main embodiment of the present invention is to provide a process for the preparation of 4-fluoro-2-methoxy-5-nitroaniline (I) or pharmaceutically acceptable salts thereof;
Formula I
Figure imgf000005_0001
which comprises:
(i) protection of 4-fluoro-2-methoxy aniline (III);
Formula III
Figure imgf000005_0002
to obtain N-protected-(4-fluoro-2-methoxyphenyl)aniline (VI);
H Formula VI p
wherein, "P" is a protecting group;
) nitration of the compound of formula (VI) to obtain N-protected-(4 fluoro-2-methoxy-5 -nitro)aniline (VII) ;
Formula VII
Figure imgf000005_0003
(iii) de-protecting of the compound of Formula (VII). In another embodiment of the present invention provides a process for the preparation of Osimertinib or a pharmaceutically acceptable salts thereof (II);
Formula II
Figure imgf000006_0001
Osimertinib
which comprises:
(i) protecting 4-fluoro-2-methoxy aniline (III);
Formula III
Figure imgf000006_0002
to obtain N-protected-(4-fluoro-2-methoxyphenyl)aniline (VI);
Formula VI
Figure imgf000006_0003
wherein, "P" is a protecting group;
(ii) nitration of the compound of formula (VI) to obtain N-protected-(4- fluoro-2-methoxy-5-nitro)aniline (VII);
Formula VII
Figure imgf000006_0004
(iii) de-protecting of the compound of Formula (VII) to obtain 4-fluoro-2- methoxy-5-nitroaniline (I);
(iv) converting 4-fluoro-2-methoxy-5-nitroaniline (I) or pharmaceutically acceptable salts thereof to Osimertinib or pharmaceutically acceptable salts thereof (II).
DETAILED DESCRIPTION OF THE INVENTION
The present invention is related to a process for the preparation of 4-fluoro-2- methoxy-5-nitroaniline (I) or pharmaceutically acceptable salts thereof.
The process comprises, 4-fluoro-2-methoxy aniline (III) is protected to obtain N- protected-(4-fluoro-2-methoxyphenyl)aniline (VI) .
The N-protecting group comprises acetyl (Ac), carbobenzyloxy (Cbz or Z) group, -methoxybenzyl carbonyl (Moz or MeOZ) group, Allyl carbamate (Alloc) group, benzoyl (Bz) group, benzyl (Bn) group, carbamate group, 2,2,2-trichloroethyl carbamate (Troc) group, />-methoxybenzyl (PMB) group, 3,4- dimethoxybenzyl (DMPM) group, / methoxyphenyl (PMP) group, tosyl (Ts) group, 2-trimethylsilylethyl carbamate (Teoc) group or other sulfonamides (Nosyl & Nps) groups and the like.
The above reaction is carried out using corresponding carbonyl compounds such as acetic anhydride, acetyl chloride, BnOCOCl or (BnOCO)20, allyl chloroformate or (Alloc)20, benzoyl chloride, benzyl halide (BnCl or BnBr), carbamic acid, 2,2,2-trichloroethyloxy carbonyl chloride, PMB trichloroacetimidate, 2,4-dimethoxybenzaldehyde, p-methoxybenzyl chloride, tosyl chloride, 2-trimethylsilylethyloxy carbonyl chloride (Teo-Cl) or Teoc-N3.
The n-protection may be carried out in presence of an acid or a base.
The acid comprises an organic acid selected from formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, oxalic acid, lactic acid, malic acid, citric acid, benzoic acid, carbonic acid, methane sulfonic acid and p- toluene sulfonic acid or a inorganic acid selected from hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, boric acid, hydrofluoric acid, hydrobromic acid, perchloric acid and hydroiodic acid or mixtures thereof. The base comprises an organic base selected from pyridine, triethylamine, methyl amine, imidazole, benzimidazole, histidine, phosphazene and 2,6-Lutidine or a inorganic base selected from potassium methoxide, potassium ethoxide, potassium tertiary butoxide, sodium methoxide, sodium ethoxide, sodium tertiary butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate, potassium acetate or ammonia, ammonium hydroxide, ammonium carbonate or mixtures thereof.
The above reaction is carried out in the presence/absence of a solvent. The solvent comprises water, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, toluene, benzene, o-xylene, m-xylene, p-xylene, acetone, acetonitrile, ethyl acetate, methylene chloride, dioxane, DMF, THF or mixture thereof.
The compound (VI) is isolated as a solid or as such used in next step. Optionally, Compound (VI) is subjected to purification either by column chromatography or by crystallization.
Still another embodiment of the present invention is N-protected-(4-fluoro-2- methoxyphenyl)aniline (VI) undergoes nitration in presence of nitrating agent to obtain N-protected-(4-fluoro-2-methoxy-5-nitro)aniline (VII).
The nitrating agent used in the above reaction comprises nitric acid, sodium nitrate, potassium nitrate and/ or acid. The acid comprises hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, boric acid, hydrofluoric acid, hydrobromic acid, perchloric acid and hydroiodic acid or mixtures thereof. The above nitration is carried out in presence/absence of a solvent. The solvent comprises of benzene, toluene, xylene, chlorobenzene, chlorotoluene, chloroform, carbon tetrachloride and water or mixtures thereof. The compound (VII) is isolated as a solid or as such used in next step. Optionally, Compound (VII) is subjected to purification either by column chromatography or by crystallization.
Yet another embodiment of the present invention is de-protection of N-protected- (4-fluoro-2-methoxy-5-nitro)aniline (VII) to obtain 4-fluoro-2-methoxy-5- nitroaniline (I) or pharmaceutically acceptable salts thereof.
The above reaction is carried out in presence of an acid, a base or a reducing agent.
The acid used in the above reaction comprises hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, boric acid, hydrofluoric acid, hydrobromic acid, perchloric acid and hydroiodic acid, Periodic acid and trichloroisocyanuric acid, trifluoro acetic acid or mixtures thereof.
The base used in the above reaction comprises ammonia, methylamine, morpholine, diisopropylethyl amine, ammonium cerium(IV) nitrate (CAN), sodium in liquid ammonia or sodium naphthalenide, samarium iodide, tributyltin hydride or mixtures thereof.
The reducing agent used in the above reaction comprises palladium-on-carbon (Pd/C), Tetrakis(triphenylphosphine)palladium(0), nickel nanoparticles immobilized on hierarchical zeolite, platinum(IV) oxide, iron in acidic media such as acetic acid, formic acid, hydrochloric acid, hydrobromic acid and the like; sodium hydrosulfite, sodium sulfide, tin(II) chloride, titanium(III) chloride, zinc, rhodium, ruthenium and nickel catalysts such as raney nickel or urushibara nickel. The above reaction is carried out in the presence/absence of a solvent. The solvent comprises an alcohol selected from Ci-Cio straight or branched chain alcohol such as methanol, ethanol, isopropyl alcohol, l-butanol,2-butanol, 2-methyl-2- propanol, 1-pentanol, 2-pentanol, 2,2-dimethyl-l-propanol, 2,2,2-trimethyl ethanol, 1-decanol, benzyl alcohol; hydrocarbon solvent selected from the group toluene, benzene, o-xylene, m-xylene, p-xylene, water, acetone, acetonitrile, ethyl acetate; methylene chloride, DMF, dioxane, THF or mixture thereof.
The compound (I) is isolated as a solid or as such used in next step. Optionally, Compound (I) is subjected to purification either by column chromatography or by crystallization.
Yet another embodiment of the present invention is 4-fiuoro-2-methoxy-5- nitroaniline (I) or pharmaceutically acceptable salts thereof as produced by the process described above, and is converted to Osimertinib or pharmaceutically acceptable salts thereof (II) by known process.
In another embodiment, 4-fiuoro-2-methoxy aniline (III) used in the present invention is prepared by reacting 2,4-difluoro nitrobenzene (VIII) with methanol in presence of a base to produce 4-fluoro-2-methoxy nitrobenzene (IX), which is reduced to give 4-fluoro-2-methoxy aniline (III).
The process is as shown in Scheme-IV below:
Figure imgf000010_0001
Scheme-IV
The base used in above reaction comprises alkali metal alkoxide selected from potassium methoxide, potassium ethoxide, potassium tertiary butoxide, sodium methoxide, sodium ethoxide, sodium tertiary butoxide, alkali metal hydroxide selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, alkali metal carbonate selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, alkali metal acetate selected from sodium acetate, potassium acetate or ammonia, ammonium hydroxide, ammonium carbonate or mixtures thereof.
The above reaction is carried out in the presence/absence of a solvent. The solvent comprises hydrocarbon selected from toluene, benzene, o-xylene, m-xylene, p- xylene, water, methanol, ethanol, propanol, isopropanol, butanol or isobutanol, acetone, acetonitrile, ethyl acetate, methylene chloride, Dimethyl formamide (DMF), Tetrahydrofuran (THF) or mixture thereof.
The compound (IX) is isolated as a solid or as such used in next step. Optionally, Compound (IX) is subjected to purification either by column chromatography or by crystallization.
The reduction is carried out using a hydrogenation catalyst comprises, nickel nanoparticles immobilized on hierarchical zeolite, palladium-on-carbon, platinum(IV) oxide, Fe/NH4C1 or iron in acidic media such as acetic acid, formic acid, hydrochloric acid, hydrobromic acid and the like; sodium hydrosulfite, sodium sulfide, tin(II) chloride, titanium(III) chloride, zinc, rhodium, ruthenium and nickel catalysts such as raney nickel or urushibara nickel.
The above reduction is carried out in the presence/absence of a solvent. The solvent selected from Ci-Cio straight or branched chain alcohol such as methanol, ethanol, isopropyl alcohol, l-butanol,2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 2,2-dimethyl-l -propanol, 2,2,2-trimethyl ethanol, 1-decanol, benzyl alcohol; toluene, benzene, o-xylene, m-xylene, p-xylene, water, acetone, acetonitrile, ethyl acetate, methylene chloride, dioxane, DMF, THF or mixture thereof. The following example(s) illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention. Example-l:
Process for the preparation of 4-fluoro-2-methoxy-5-nitroaniIine:
Step-A— process for the preparation of 4-fluoro-2-methoxy-l-nitrobenzene: Toluene (500 ml) was added into clean and dry round bottom flask, then 2,4- difluoro-1 -nitrobenzene (500 gms) was added. The reaction mass was cooled to 0°C then methanol (100 ml) was slowly added to reaction mass at 0°C. To the reaction mass potassium tert-butoxide (PTB) (353 gms) was added in lots (10 lots) at 0°C. The reaction mass was stirred at 0°C for 15-30 minutes, then temperature raised to 20°C and the reaction mass was stirred at 20°C for 4 hrs. The reaction mass was decomposed in water (1500 ml). The contents were stirred for 10-15 minutes followed by toluene was added to the reaction mass. The layers were separated, and the aqueous layer was extracted with toluene followed by separated the organic layer. Total organic layer was washed with water (1000 ml). The organic layer was then washed with brine solution (NaCl (50 gms) + water (500 ml)) and dried over sodium sulphate. The solvent was distilled out under vacuum. Petroleum ether (1000 ml) was added to the residue and the contents were cooled to below 10°C then stirred for 30 minutes. The solid was filtered off and washed with petroleum ether (200 ml). The solid was dried at 50-60°C for 3-5 hrs (Yield - 470 gms; 87.38%).
Step-B - process for the preparation of 4-fluoro-2-methoxyaniline:
In an autoclave methanol (4000 ml) and 4-fluoro-2-methoxy-l -nitrobenzene (470 gms) were added. A mixture of Raney Ni (47 gms) and methanol (470 ml) was added to the reaction mass under nitrogen atmosphere. The reaction mass was stirred at 25-30°C for 10-15 minutes. Hydrogen gas was slowly fed into the autoclave upto 3.0 kgs (slight exothermic temperature observed). The reaction mass was stirred at 25-30°C for 8-10 hrs till there was no hydrogen consumption. The reaction mass was filtered through celite and the celite bed was washed with methanol (250 ml). Organic solvent was distilled under vacuum to give black color liquid (Yield - 380 gms; 98.0%).
Step-C - Process for the preparation of N-(4-fluoro-2-methoxy phenyl) acetamide:
In a dry round bottom flask acetic acid (950 ml) and 4-fluoro-2-methoxyaniline (380 gms) were added. The reaction mass was stirred at 25-30°C for 10-15 minutes. Acetic anhydride (439 gms) was added slowly to the reaction mass at 25- 35°C in 1.0-2.0 hrs. The reaction mass was heated to 90°C and stirred at same temperature for 3.0-5.0 hrs. The reaction mass was decomposed into water (1000 ml) and stirred at 25-30°C for 1.0-2.0 hrs. The solid was filtered and washed with water (300 ml). The reaction mass was extracted with ethyl acetate (2000 ml). Total organic layers were washed with NaHC03 solution (NaHC03 (100 gms) + water-4 (500 ml)) followed by washed with water (1000 ml), then washed with brine solution (NaCl (50 gms) + water-6(250 ml)) and dried over sodium sulphate (200 gms). The solvent was distilled out under vacuum. Petroleum ether (500 ml) was added to the residue and cooled to below 10°C and stirred for 30 minutes. The solid was filtered off and washed with petroleum ether (150 ml). The solid was dried at 50-60°C for 3-5 hrs (Yield - 410 gms; 83.13%).
Step D - process for the preparation of N-(4-fluoro-2-methoxy-5-nitrophenyl) acetamide:
In a dry round bottom flask sulfuric acid (1025 ml) and N-(4-fluoro-2- methoxyphenyl)acetamide (410 gms) were added. The reaction mass was cooled to 0°C. Fuming nitric acid was added to reaction mass at 0-5°C in 4-6 hrs and stirred at 0°C for 1.0-2.0 hrs. The reaction mass was slowly decomposed into chilled water (3500 ml). The reaction mass was stirred for 1.0 - 2.0 hrs. The reaction mass was stirred at 25-35°C for 3.0 hrs. The solid was filtered, washed with water (1000 ml) and dried at 50-60°C for 3-5 hrs (Yield - 400 gms; 78.30%). Step E - Process for the preparation of 4-fluoro-2-methoxy-5-nitroaniline:
In a clean and dry round bottom flask methanol (400 ml) and N-(4-fluoro-2- methoxy-5-nitrophenyl)acetamide (400 gms) were added. Hydrochloric acid was added to the reaction mass at 25-35°C. The reaction mass was then heated to reflux and stirred at reflux for 3.0-5.0 hrs. The solvent was completely distilled out under vacuum, and cooled the reaction mass to 10°C and stirred for 2.0-3.0 hrs. The solid was filtered and taken into another round bottom flask then water (500 ml) added. The reaction mass pH was adjusted to 9.0 with NaOH solution and the reaction mass was extracted with ethyl acetate (2000 ml). The organic layer was washed with brine solution (NaCl (100 gms) + water-2(500 ml)) and dried over sodium sulphate. The solvent was distilled out under vacuum. Petroleum ether (1000 ml) was added to the residue, cooled to below 10°C and stirred for 30 minutes. The solid was filtered, and washed with petroleum ether (250 ml) and finally dried at 50-60°C for 3-5 hrs (Yield - 240 gms; 73.55%).

Claims

CLAIM:
A process for the preparation of 4-fluoro-2-methoxy-5-nitroaniline (I) pharmaceutically acceptable salts thereof;
Formula I
Figure imgf000015_0001
which comprises:
(i) protection of 4-fluoro-2-methoxy aniline (III);
Formula III
Figure imgf000015_0002
to obtain N-protected-(4-fluoro-2-methoxyphenyl)aniline (VI);
Figure imgf000015_0003
Formula VI wherein, "P" is a protecting group; nitration of the compound of formula (VI) to obtain N-protected-(4- fluoro-2-methoxy-5 -nitro)aniline (VII) ;
Formula VII
Figure imgf000015_0004
(iii) de-protecting the compound of Formula (VII) to produce 4-fluoro-2- methoxy-5-nitroaniline (I) or pharmaceutically acceptable salts thereof.
The process as claimed in claim 1, wherein the protection in step-(i) is carried out in presence of an acid or a base.
The process as claimed in claim 2, wherein the acid comprises an organic acid selected from formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, oxalic acid, lactic acid, malic acid, citric acid, benzoic acid, carbonic acid, methane sulfonic acid and p-toluene sulfonic acid; or a inorganic acid selected from hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, boric acid, hydrofluoric acid, hydrobromic acid, perchloric acid and hydroiodic acid or mixtures thereof. The process as claimed in claim 2, the base comprises an organic base selected from pyridine, triethylamine, methyl amine, imidazole, benzimidazole, histidine, phosphazene and 2,6-Lutidine; or a inorganic base selected from potassium methoxide, potassium ethoxide, potassium tertiary butoxide, sodium methoxide, sodium ethoxide, sodium tertiary butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate, potassium acetate or ammonia, ammonium hydroxide, ammonium carbonate or mixtures thereof.
The process as claimed in claim 1, the nitration in step-(ii) is carried out using a nitrating agent comprises nitric acid, sodium nitrate, potassium nitrate; and/or an acid comprises hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, boric acid, hydrofluoric acid, hydrobromic acid, perchloric acid and hydroiodic acid or mixture thereof. The process as claimed in claim 1 , wherein the de-protection step-(iii) is carried out in presence of an acid, a base or a reducing agent.
The process as claimed in claim 6, wherein the acid comprises hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, boric acid, hydrofluoric acid, hydrobromic acid, perchloric acid and hydroiodic acid, Periodic acid and trichloroisocyanuric acid, trifluoro acetic acid or mixture thereof; the base comprises ammonia, methylamine, morpholine, diisopropylethyl amine, ammonium cerium(IV) nitrate (CAN), sodium in liquid ammonia or sodium naphthalenide, samarium iodide, tributyltin hydride or mixture thereof.
The process as claimed in claim 6, wherein the reducing agent comprises palladium-on-carbon (Pd/C), Tetrakis(triphenylphosphine)palladium(0), nickel nanoparticles immobilized on hierarchical zeolite, platinum(IV) oxide, iron in acidic media such as acetic acid, formic acid, hydrochloric acid, hydrobromic acid and the like; sodium hydrosulfite, sodium sulfide, tin(II) chloride, titanium(III) chloride, zinc, rhodium, ruthenium and nickel catalysts such as raney nickel or urushibara nickel.
The process as claimed in claim 1 , the reaction of each step-(i) to step-(iii) is carried out in the presence/absence of a solvent; wherein the solvent(s) comprises an alcohol selected from Ci-Cio straight or branched chain alcohol such as methanol, ethanol, isopropyl alcohol, 1-butanol, 2-butanol, 2-methyl- 2-propanol, 1-pentanol, 2-pentanol, 2,2-dimethyl-l-propanol, 2,2,2-trimethyl ethanol, 1-decanol, benzyl alcohol; hydrocarbon solvent selected from toluene, benzene, o-xylene, m-xylene, -xylene; chlorobenzene, chlorotoluene, chloroform, carbon tetrachloride water, acetone, acetonitrile, ethyl acetate, methylene chloride, DMF, dioxane, THF or mixture thereof.
A process for the preparation of Osimertinib or a pharmaceutically acceptable salts thereof (II); Formula II
Figure imgf000018_0001
Osimertinib
which comprises:
(i) protecting 4-fluoro-2-methoxy aniline (III);
Formula III
Figure imgf000018_0002
to obtain N-protected-(4-fluoro-2-methoxyphenyl)aniline (VI);
Formula VI
Figure imgf000018_0003
wherein, "P" is a protecting group;
(ii) nitration of the compound of formula (VI) to obtain N-protected-(4- fluoro-2-methoxy-5 -nitro)aniline (VII) ;
Formula VII
Figure imgf000018_0004
(iii) de-protecting of the compound of Formula (VII) to obtain 4-fluoro-2- methoxy-5-nitroaniline (I); converting 4-fluoro-2-methoxy-5-nitroaniline (I) or pharmaceutically acceptable salts thereof to Osimertinib or pharmaceutically acceptable salts thereof (II).
PCT/IB2018/053246 2017-05-11 2018-05-10 A process for the preparation of 4-fluoro-2-methoxy-5-nitroaniline WO2018207120A1 (en)

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CN104817541A (en) * 2015-05-11 2015-08-05 苏州东南药业股份有限公司 Synthetic method of anti-tumor medicine
CN106366022A (en) * 2016-08-19 2017-02-01 上海工程技术大学 Intermediate used for AZD9291 preparation, and preparation method and application thereof

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