WO2007074474A1 - Novel intermediates for preparation of letrozole - Google Patents

Novel intermediates for preparation of letrozole Download PDF

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Publication number
WO2007074474A1
WO2007074474A1 PCT/IN2006/000491 IN2006000491W WO2007074474A1 WO 2007074474 A1 WO2007074474 A1 WO 2007074474A1 IN 2006000491 W IN2006000491 W IN 2006000491W WO 2007074474 A1 WO2007074474 A1 WO 2007074474A1
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Prior art keywords
formula
compound
process according
letrozole
acid
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PCT/IN2006/000491
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French (fr)
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Shiv Kumar Agarwal
Golak Chandra Maikap
Pradipta Kumar
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Dabur Pharma Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • the present invention relates to novel intermediates useful for preparation of the aromatase inhibitor, Letrozole.
  • the present invention further relates to a process for preparation of the novel intermediates.
  • Letrozole is one of a new class of drugs known as aromatase inhibitors, which functions by reducing body levels of estrogen in postmenopausal women. It is a type of hormonal therapy that is used in the treatment of breast cancer in women who have had their menopause phase.
  • Patel et al in WO 2004/076409 disclose another process for the preparation of Letrozole which comprises of reacting 4-halomethylbenzonitrile (1) with 4-amino-l,2,4-triazole (4) to give 4- [(4-amino-4H-l, 2,4-triazolium-l-yl) methyl] benzonitrile halide (5), which on de-amination gives 4- [1- (1 H-I, 2,4-triazol-l-yl) methylene] benzonitrile (3). Reaction of this compound with 4-fluorobenzonitrile gives Letrozole (I). The chemistry for this process is summarised in Scheme-II.
  • the compound (3) thus obtained is further converted to Letrozole (I) by conventional methods.
  • Letrozole (I) could be synthesized by a novel method different from that of the prior art methods through utilization of novel intermediates, which forms the basis of the present invention.
  • the method differs from the prior art methods in that, first a dibenzo methyl nucleus is created, which is further elaborated to Letrozole, unlike the prior art methods wherein the dibenzo methyl nucleus is created in the final stages of Letrozole synthesis.
  • the precursor dibenzo methyl compounds are novel and valuable intermediates for Letrozole.
  • Letrozole (I) can be obtained by the use of four novel intermediates individually represented by formula (Ha) , (lib) , (lie) and (Hd),
  • the compound of formula (Ha) can be prepared from the benzhydrol compound of formula (9) by reaction with 1 (H) 1,2,4- triazole (2) in the presence of a solvent and in the presence of an acid.
  • the compound of formula (lib) can be prepared from (Ha) by oxidation with a suitable oxidizing agent in presence of acetic anhydride and a mineral acid.
  • the compound of formula (lie) can be prepared from (lib) by treatment with a solution of an alkali metal hydroxide in alcoholic solvents (C 1 to C 6 ).
  • the compound of formula (Hd) can be prepared from (lie) by reaction with hydroxylamine hydrochloride in an appropriate alcoholic solvent.
  • compound of formula (Hd) can be directly prepared from (lib) by treatment with hydroxylamine hydrochloride in a suitable alcoholic solvent
  • Letrozole (I) can be prepared from compound (Hd) by dehydration reaction in presence of acetic acid and acetic anhydride.
  • the intermediate compound ⁇ - (IH-I, 2,4-Triazolyl) - 4,4'- dimethyldiphenylmethane (Ha) is prepared by a modified Ritter reaction between benzhydrol derivative i.e. 4,4-Dimethyl benzhydrol (9), and 1 (H)-l,2,4-triazole
  • any organic solvent that is capable of dissolving the benzhydrol compound (9) can be employed, however, halogenated hydrocarbons are preferred.
  • Suitable halogenated hydrocarbons that can be employed include
  • Dichloromethane Dichloroethane, Carbon tetrachloride, Chloroform and the like.
  • 1,2 dichloroethane is more preferred.
  • IH- 1,2,4, triazole compound (2) is employed in excess and can be employed in molar equivalents of 1.0-50 moles per mole of Compound (9) and preferably in molar equivalents of 15-20 moles per mole of Compound (9).
  • the acid that can be employed can be either an organic or an inorganic acid, preferably an inorganic acid.
  • Suitable inorganic acid includes HCl, H 2 SO 4 , H 3 PO 4 , HNO 3 and the like.
  • the reaction temperature can be in the range of -50 to +10 0 C.
  • a temperature in the range of —20 to +1O 0 C is employed.
  • Benzhydrol compound (9) can be obtained by reduction of corresponding keto compounds through suitable methods.
  • the intermediate compound ⁇ - (IH-I, 2,4-Triazolyl) - 4,4'- dimethylidinetetraacetoxy diphenylmethane (lib) is prepared by reaction of ⁇ - (IH-I, 2,4-Triazolyl) - 4,4'-dimethyldiphenylmethane (Ha) with a suitable oxidizing agent, acetic anhydride and a mineral acid.
  • suitable oxidizing agents that can be employed include chromyl chloride, chromyl acetate, chromium trioxide and the like.
  • chromium trioxide is more preferred and is employed in molar equivalents of 2 to 20 moles per mole of Compound (Ha) and preferably in molar equivalents of 3 to 6 moles per mole of Compound (Ha).
  • Suitable mineral acids that can be employed include HCl, H 2 SO 4 , H 3 PO 4 , and the like.
  • the reaction temperature can be in the range of -70 to +20°C. Preferably, a temperature in the range of -20 to 20°C is employed.
  • ⁇ - (IH-I, 2,4-Triazolyl) - 4,4'- dimethyldiphenylmethane (Ha) was reacted with oxidizing agent chromium trioxide in a molar ratio about 4 M per mole of compound (Ha) and acetic anhydride and a mineral acid in a molar ratio between 7 to 8 moles per moles of compound (Ha), at a temperature about -10 to -15°C gives the ⁇ - (IH-I, 2,4-
  • the intermediate compound ⁇ - (IH-I, 2,4-Triazolyl) - 4,4'-diformyl diphenylmethane (lie) is prepared by reaction of ⁇ - (IH-I, 2,4-Triazolyl) - 4,4'- dimethylidinetetraacetoxy diphenylmethane (lib) with alcoholic solution of alkali metal hydroxides at a temperature between 20-25 °C.
  • Alkali metal hydroxides that can be employed include Lithium hydroxides,
  • potassium hydroxide is more preferred and is employed in excess. It can be employed in the molar equivalents of 2 to 20 moles per mole of Compound (lib) and preferably in molar equivalents of 3 to 6 moles per mole of Compound (lib).
  • ⁇ - (IH-I, 2,4-Triazolyl) - 4,4'-diformyl diphenylmethane (lie) can also be prepared by carrying out the reaction in alcoholic solution concentrated with a mineral acid.
  • a preferred alcoholic solvent includes methanol, ethanol, isopropanol and the like.
  • ⁇ - (IH-I, 2,4-Triazolyl) - 4,4'- dimethylidinetetraacetoxy diphenylmethane (lib) was reacted with potassium hydroxide in a molar ratio about 4 M with respect to (lib) in methanolic solvent medium, and Sulphuric acid at temperature about 22-25°C to give ⁇ - (IH-I, 2,4- Triazolyl) - 4,4'-diformyl diphenylmethane (lie).
  • Suitable alcohol solvents include methanol, ethanol, isopropanol and the like.
  • Alkali metal hydroxides that can be employed include sodium hydroxide, potassium hydroxide, and the like. Amongst the alkali metal hydroxides, potassium hydroxide is more preferred and is employed in excess. It can be employed in the molar equivalents of 2 to 10 moles per mole of Compound (lie) and preferably in molar equivalents of about 4 moles per mole of Compound (lie).
  • the di-oxime derivative (Hd) can also be obtained directly by reaction of ⁇ - (IH-I, 2,4-Triazolyl) - 4,4'-dimethylidinetetraacetoxy diphenylmethane (lib) with hydroxylamine hydrochloride in a suitable alcohol (C1-C6) medium under continuous refluxing for 2 to 6 hrs without isolating the di-formyl intermediate (lie).
  • ⁇ - (IH-I, 2,4-Triazolyl) - 4,4'-diformyl diphenylmethane (lie) is condensed with hydroxylamine hydrochloride in a molar ratio of about 4 M per mole of Compound (lie) in isopropanol medium (previously neutralized with potassium hydroxide) at a temperature about 80 to 85°C to give ⁇ - (IH-I, 2,4-Triazolyl) - 4,4'-diformaldoxime diphenylmethane (Hd).
  • Letrozole (I) is prepared by reaction of ⁇ - (IH-I, 2,4-Triazolyl) - 4,4'- diformaldoxime diphenylmethane (Hd) with acetic anhydride and sodium acetate in acetic acid medium, which is further, purified chromatographically.
  • ⁇ - (IH-I, 2,4-Triazolyl) - 4,4'-diformaldoxime diphenylmethane (Hd) is reacted with acetic anhydride and sodium acetate in a molar ratio about 5 M per moles of (Hd) in acetic acid medium at a temperature between 50 to 150°C, more preferably about 110°C to give the 4,4'-(1H-I, 2,4- triazol-lyl-methylene)-bisbenzonitrile/Letrozole (I).
  • the Compound (I) i.e. Letrozole thus obtained exhibits the following spectral characteristics:
  • reaction mixture was adjusted to PH ⁇ 7 and methanol was recovered on a rota- evaporator under reduced pressure to give an oily mass which was diluted with water (500ml) and cooled to 10 - 15 0 C to give a solid. The solid was filtered and washed with water and dried (50g, M.Pt. 70 - 72 0 C.)
  • reaction mixture was further stirred for 4h
  • the reaction mixture was poured into 2L of water and extracted with ethyl acetate (IL).

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Abstract

The invention provides novel intermediates of formula (II), wherein R1 and R2 are same and are selected from methyl, CH (OCOCH3) 2, CHO or CH=N-OH, a process for preparation thereof and a process for preparation of Letrozole of formula (I), utilizing the said novel intermediates of formula (II).

Description

NOVEL INTERMEDIATES FOR PREPARATION OF LETROZOLE
FIELD OF THE INVENTION
The present invention relates to novel intermediates useful for preparation of the aromatase inhibitor, Letrozole. The present invention further relates to a process for preparation of the novel intermediates.
BACKGROUND OF THE INVENTION
Letrozole is one of a new class of drugs known as aromatase inhibitors, which functions by reducing body levels of estrogen in postmenopausal women. It is a type of hormonal therapy that is used in the treatment of breast cancer in women who have had their menopause phase.
Many breast cancers rely on supplies of the hormone "oestrogen" to increase. In women who have had their menopause, the main source of oestrogen is through changing androgens (sex hormones produced by the adrenal glands) into oestrogen. This is carried out by an enzyme called aromatase. The conversion process is known as aromatisation, and happens mainly in the fatty tissues of the body. Letrozole blocks this process and reduces the amount of oestrogen in the body. For this reason letrozole is known as an aromatase inhibitor.
Bowman et al in US 4,978,672; US 5,352,795; and US 5,473,078 disclose a process for preparation of Letrozole which comprises of reacting 4-bromomethylbenzonitrile (1) with IH- 1,2, 4-triazole (2) to yield 4- [1- (1, 2, 4-triazol-l- yl) methyl] benzonitrile (3), which is then reacted with 4-fluorobenzonitrile to give the crude Letrozole (I).
The crude Letrozole thus obtained is crystallized from ethanol or ether / ethyl acetate to give Pure Letrozole.
The chemistry is summarised in Scheme-I. 4-Brom -ylmethyl)
Figure imgf000003_0001
Figure imgf000003_0002
PURE LETROZOLE Letrozole Crude (|)
Scheme-I: Process disclosed in US 4,978,672/ '5,352,795 / 5,473,078 for preparation of Letrozole
Patel et al in WO 2004/076409 disclose another process for the preparation of Letrozole which comprises of reacting 4-halomethylbenzonitrile (1) with 4-amino-l,2,4-triazole (4) to give 4- [(4-amino-4H-l, 2,4-triazolium-l-yl) methyl] benzonitrile halide (5), which on de-amination gives 4- [1- (1 H-I, 2,4-triazol-l-yl) methylene] benzonitrile (3). Reaction of this compound with 4-fluorobenzonitrile gives Letrozole (I). The chemistry for this process is summarised in Scheme-II.
Figure imgf000004_0001
(I) 4-(lH-l,2,4-triazol-l-ylmetliyl) benzonitrile
Recrystallisation using hot Ethyl acetate
Letrozole 99.90 % Pure
Scheme-II: Process disclosed in PCT Application WO 2004/076409 for preparation of Letrozole
Wadhwa et al in US Application 2005/0209294, disclose an improved method for preparation of compound (3), the improvement comprising reaction of 4-(1H-1, 2,4- triazol-1-yl methyl) benzonitrile with an alkali metal salt of 1 ,2,4-triazole (6). The compound (3) thus obtained is further converted to Letrozole (I) by conventional methods.
The chemistry disclosed is summarised in Scheme-Ill.
Figure imgf000005_0001
Scheme-Ill: Process disclosed in US Application 2005/0209294 for preparation of Letrozole
The present inventors have found that Letrozole (I) could be synthesized by a novel method different from that of the prior art methods through utilization of novel intermediates, which forms the basis of the present invention.
In particular, the method differs from the prior art methods in that, first a dibenzo methyl nucleus is created, which is further elaborated to Letrozole, unlike the prior art methods wherein the dibenzo methyl nucleus is created in the final stages of Letrozole synthesis.
The precursor dibenzo methyl compounds are novel and valuable intermediates for Letrozole.
More specifically, the present inventors have found that the synthesis of Letrozole (I) can be obtained by the use of four novel intermediates individually represented by formula (Ha) , (lib) , (lie) and (Hd),
(Ha)
Figure imgf000005_0002
Figure imgf000006_0001
Figure imgf000006_0002
which can be collectively represented by formula-II,
Figure imgf000006_0003
(II) wherein R1 and R2 are same and are selected from methyl, CH (OCOCH3) 2, CHO or CH=N-OH SUMMARY OF THE INVENTION
Thus the present invention relates to compound of formula II,
Figure imgf000007_0001
wherein R1 and R2 are same and are selected from methyl, CH (OCOCH3) 2, CHO or CH=N-OH and salts thereof.
According to another aspect of the invention there is provided process for preparation of Letrozole of formula (I),
Figure imgf000007_0002
comprising the steps of: a. reacting 4,4-Dimethyl benzhydrol (9), with (lH)-l,2,4-triazole (2)
Figure imgf000007_0003
in presence of a halogenated hydrocarbon and an acid to give compound of formula (Ha);
Figure imgf000008_0001
b. if desired, effecting oxidation of compound of formula (Ha) with an oxidizing agent in the presence of acetic anhydride and a mineral acid to give compound of formula (lib);
Figure imgf000008_0002
c. if desired treating the compound of formula (lib) with a solution of an alkali metal hydroxide in an alcohol or with a solution of a mineral acid in an alcohol to give compound of formula (lie);
Figure imgf000008_0003
lie d. if desired, reacting the compound of formula (lie) with hydroxylamine hydrochloride in an alcoholic solvent to give compound of formula (Hd); and
Figure imgf000009_0001
e. if desired, reacting the compound of formula (Hd) with acetic anhydride and sodium acetate in acetic acid to give Letrozole of formula (I).
Figure imgf000009_0002
The representative compounds that are encompassed under formula (II) are summarized in Table- 1.
Table-1: The representative compounds encompassed under formula (II)
Figure imgf000009_0003
According to a further aspect of the invention the compound of formula (Ha) can be prepared from the benzhydrol compound of formula (9) by reaction with 1 (H) 1,2,4- triazole (2) in the presence of a solvent and in the presence of an acid. According to yet another aspect of the invention the compound of formula (lib) can be prepared from (Ha) by oxidation with a suitable oxidizing agent in presence of acetic anhydride and a mineral acid.
According to a still further aspect of the invention the compound of formula (lie) can be prepared from (lib) by treatment with a solution of an alkali metal hydroxide in alcoholic solvents (C1 to C6).
According to a still further aspect of the invention the compound of formula (Hd) can be prepared from (lie) by reaction with hydroxylamine hydrochloride in an appropriate alcoholic solvent.
Alternatively, compound of formula (Hd) can be directly prepared from (lib) by treatment with hydroxylamine hydrochloride in a suitable alcoholic solvent
According to yet further aspect of the invention Letrozole (I) can be prepared from compound (Hd) by dehydration reaction in presence of acetic acid and acetic anhydride.
DETAILED DESCRIPTION OF THE INVENTION
The process of the present invention is detailed as under:
A. Preparation of α - (IH-I, 2,4-Triazolyl) - 4,4'-dimethyldiphenylmethane (Ha):
The intermediate compound α - (IH-I, 2,4-Triazolyl) - 4,4'- dimethyldiphenylmethane (Ha) is prepared by a modified Ritter reaction between benzhydrol derivative i.e. 4,4-Dimethyl benzhydrol (9), and 1 (H)-l,2,4-triazole
(2) in an organic solvent and in the presence of an acid.
While, any organic solvent that is capable of dissolving the benzhydrol compound (9) can be employed, however, halogenated hydrocarbons are preferred.
Suitable halogenated hydrocarbons that can be employed include
Dichloromethane, Dichloroethane, Carbon tetrachloride, Chloroform and the like.
Amongst the halogenated hydrocarbon solvents, 1,2 dichloroethane is more preferred. IH- 1,2,4, triazole compound (2) is employed in excess and can be employed in molar equivalents of 1.0-50 moles per mole of Compound (9) and preferably in molar equivalents of 15-20 moles per mole of Compound (9).
The acid that can be employed can be either an organic or an inorganic acid, preferably an inorganic acid.
Suitable inorganic acid includes HCl, H2SO4, H3PO4, HNO3 and the like. The reaction temperature can be in the range of -50 to +100C. Preferably, a temperature in the range of —20 to +1O0C is employed.
In a typical embodiment, to a solution of compound (9) in 1,2-diGhloroethane, cooled to a temperature about -2O0C is added l(H) 1,2,4-triazole (2) (about 15 M equivalents) followed by addition of acid and allowing the reaction to proceed between a temperature of —20 to +100C. The product can be isolated by conventional methods.
The Compound (Ha) thus obtained exhibits the following spectral characteristics:
IR (KBr) (v Cm"1): 1513.5, 1431.6
1H NMR (CDCl3): δ 8.0 (s, IH), 7.9 (s, IH), 7.25 - 7.15 (m, 4H), 7.02 - 7.00 (m, 4H) 6.68 (s, IH), 2.34 (s, 12H).
Mass Spectrum: [M4Na], 286
The starting, Benzhydrol compound (9) can be obtained by reduction of corresponding keto compounds through suitable methods.
Preparation of α - (IH-I, 2,4-TriazoryT) - 4,4'-dimethylidinetetraacetoxy diphenylmethane (lib):
The intermediate compound α - (IH-I, 2,4-Triazolyl) - 4,4'- dimethylidinetetraacetoxy diphenylmethane (lib) is prepared by reaction of α - (IH-I, 2,4-Triazolyl) - 4,4'-dimethyldiphenylmethane (Ha) with a suitable oxidizing agent, acetic anhydride and a mineral acid. Suitable oxidizing agents that can be employed include chromyl chloride, chromyl acetate, chromium trioxide and the like. Amongst the oxidizing agents, chromium trioxide is more preferred and is employed in molar equivalents of 2 to 20 moles per mole of Compound (Ha) and preferably in molar equivalents of 3 to 6 moles per mole of Compound (Ha).
Suitable mineral acids that can be employed include HCl, H2SO4, H3PO4, and the like.
The reaction temperature can be in the range of -70 to +20°C. Preferably, a temperature in the range of -20 to 20°C is employed.
In a preferred embodiment, α - (IH-I, 2,4-Triazolyl) - 4,4'- dimethyldiphenylmethane (Ha) was reacted with oxidizing agent chromium trioxide in a molar ratio about 4 M per mole of compound (Ha) and acetic anhydride and a mineral acid in a molar ratio between 7 to 8 moles per moles of compound (Ha), at a temperature about -10 to -15°C gives the α - (IH-I, 2,4-
Triazolyl) - 4,4'-dimethylidinetetraacetoxy diphenylmethane (lib).
The Compound (lib) thus obtained exhibits the following spectral characteristics: IR (KBr) (v Cm"1): 1753, 1515, 1424.5 1R NMR (CDCl3): δ 8.03 (s, IH), 7.97 (s, IH), 7.66 (s, 2H), 7.55 - 7.52 (m, 4H),
7.26 - 7.17 (m, 4H), 6.76 (s, IH), 2.12 (s, 12H). Mass Spectrum: [M+H]+ 4%6, [M+ Na]+ 518.1
C. Preparation of α - (IH-I, 2,4-Triazolyl) - 4,4'-diformyl diphenylmethane (Hc):
The intermediate compound α - (IH-I, 2,4-Triazolyl) - 4,4'-diformyl diphenylmethane (lie) is prepared by reaction of α - (IH-I, 2,4-Triazolyl) - 4,4'- dimethylidinetetraacetoxy diphenylmethane (lib) with alcoholic solution of alkali metal hydroxides at a temperature between 20-25 °C. Alkali metal hydroxides that can be employed include Lithium hydroxides,
Sodium hydroxide, potassium hydroxide, and the like. Amongst the alkali metal hydroxides, potassium hydroxide is more preferred and is employed in excess. It can be employed in the molar equivalents of 2 to 20 moles per mole of Compound (lib) and preferably in molar equivalents of 3 to 6 moles per mole of Compound (lib).
Alternatively, α - (IH-I, 2,4-Triazolyl) - 4,4'-diformyl diphenylmethane (lie) can also be prepared by carrying out the reaction in alcoholic solution concentrated with a mineral acid.
A preferred alcoholic solvent includes methanol, ethanol, isopropanol and the like.
In a typical embodiment, α - (IH-I, 2,4-Triazolyl) - 4,4'- dimethylidinetetraacetoxy diphenylmethane (lib) was reacted with potassium hydroxide in a molar ratio about 4 M with respect to (lib) in methanolic solvent medium, and Sulphuric acid at temperature about 22-25°C to give α - (IH-I, 2,4- Triazolyl) - 4,4'-diformyl diphenylmethane (lie).
The Compound (lie) thus obtained exhibits the following spectral characteristics:
IR (KBr) (v Cm-1): 1703.8, 1605.8, 1503.5
1H NMR (CDC13): δ 10.04 (s,2H), 8.08 (m, 2H5Tz), 7.93 - 7.91 (m, Ar, 4H), 7.36 - 7.27 (m,4H,Ar), 6.88 (s,lH) Mass Spectrum: [M-1], 290.2 Preparation of α - (IH-I, 2,4-Triazolyl) - 4,4'-diformaldoxime diphenylmethane did): The intermediate compound α - (IH-I, 2,4-Triazolyl) - 4,4'-diformaldoxime diphenylmethane (Hd) is prepared by reaction of α - (IH-I, 2,4-Triazolyl) - 4,4'- diformyl diphenylmethane (lie) with hydroxylamine hydrochloride in suitable alcohol solvent and an alkali metal hydroxide.
Suitable alcohol solvents include methanol, ethanol, isopropanol and the like.
Alkali metal hydroxides that can be employed include sodium hydroxide, potassium hydroxide, and the like. Amongst the alkali metal hydroxides, potassium hydroxide is more preferred and is employed in excess. It can be employed in the molar equivalents of 2 to 10 moles per mole of Compound (lie) and preferably in molar equivalents of about 4 moles per mole of Compound (lie).
Alternatively, the di-oxime derivative (Hd) can also be obtained directly by reaction of α - (IH-I, 2,4-Triazolyl) - 4,4'-dimethylidinetetraacetoxy diphenylmethane (lib) with hydroxylamine hydrochloride in a suitable alcohol (C1-C6) medium under continuous refluxing for 2 to 6 hrs without isolating the di-formyl intermediate (lie).
In a typical embodiment, α - (IH-I, 2,4-Triazolyl) - 4,4'-diformyl diphenylmethane (lie) is condensed with hydroxylamine hydrochloride in a molar ratio of about 4 M per mole of Compound (lie) in isopropanol medium (previously neutralized with potassium hydroxide) at a temperature about 80 to 85°C to give α - (IH-I, 2,4-Triazolyl) - 4,4'-diformaldoxime diphenylmethane (Hd).
The Compound (Hd) thus obtained exhibits the following spectral characteristics:
IR (KBr) ( v Cm'1): 3270, 2970, 1510, 1450 1H NMR (DMSO-d6): δ ppm 11.3 (s,2H), 8.12 (s, IH), 8.08 (s, IH), 7.61 - 7.58
(m, 4H), 7.26 - 7.24 (m,4H), 7.13 (s,lH), Mass Spectrum: [M+H]+, 322.1, [M+ Na]+, 344.1, [M" Triazole+ H]+, 254.2 Preparation of 4,4'-(1H-I, 2,4-triazol-lyl-methylene)-bisbenzonitrile/LetiOzole Ql
Letrozole (I) is prepared by reaction of α - (IH-I, 2,4-Triazolyl) - 4,4'- diformaldoxime diphenylmethane (Hd) with acetic anhydride and sodium acetate in acetic acid medium, which is further, purified chromatographically.
In a preferred embodiment, α - (IH-I, 2,4-Triazolyl) - 4,4'-diformaldoxime diphenylmethane (Hd) is reacted with acetic anhydride and sodium acetate in a molar ratio about 5 M per moles of (Hd) in acetic acid medium at a temperature between 50 to 150°C, more preferably about 110°C to give the 4,4'-(1H-I, 2,4- triazol-lyl-methylene)-bisbenzonitrile/Letrozole (I). The Compound (I) i.e. Letrozole thus obtained exhibits the following spectral characteristics:
1H NMR (CDCl3): δ ppm 8.09 (s, IH), 8.07 (s, IH), 7.72 - 7.69 (m, 4H), 7.36 -
7.27 (m, 4H), 6.84 (s, IH),
Mass Spectrum: [M-I], 284.3
The method of preparation of Letrozole as per the present invention is summarised in Scheme-IV:
- 10
Figure imgf000015_0001
Letrozole (I) lid
Scheme-IV: Preparation of Letrozole (I) as per method of the present invention
15 In the following section preferred embodiments are described by way of examples to illustrate the process of this invention. However, these are not intended in any way to limit the scope of the present invention. If not mentioned otherwise, the structure of final products, intermediates and starting material is confirmed by analytical method, e.g. Microanalysis and spectroscopic characteristics (e.g. IR, NMR, Mass Spectra)
Example - 1
Preparation of 4,4'- Dimethyl benzophenone (8)
To a solution of p-Toluoyl chloride (5Og, 0.32 mol) in toluene (250ml) cooled to -5 °C. was added Aluminium chloride (75.5g, 0.56 mol) in lots over a period of Ih maintaining temperature between -5 to 0°C. after complete addition of Aluminium chloride, the reaction was further stirred for 5 - 6h to ensure complete consumption of p-toluoyl chloride (by HPLC).
The reaction mixture was then slowly poured in to a mixture of crashed ice (1.5 Kg) and cone. HCl (750ml) maintaining temperature between 0 to 1O0C. The products were extracted into ethyl acetate (1000 ml). The ethyl acetate layer was separated and washed with water to neutral PH (6 - 7). Finally ethyl acetate was concentrated on a rota evaporator to give 4,4'-dimethyl benzophenone as a solid (5Og, M.Pt. 90- 930C)
1H NMR (CDCl3): δ 7.74 - 7.70 (m, 4H), 7.31 - 7.28 (m5 4H), 2.46 (s, 6H). Mass Spectrum: [M+l], 211
Example - 2
Preparation of 4,4'- Dimethyl benzhydrol (9)
To a solution of 4,4 '-dimethyl benzophenone obtained from experiment 1 (50g, 0.23 mol) in methanol (1500 ml) at ambient temperature was added Sodium borohydride (15g, 0.39 mol) in lots maintaining temperature at 30 - 35°C. After complete addition of sodium borohydride, the reaction mixture was stirred for further 30 min.
The reaction mixture was adjusted to PH ~7 and methanol was recovered on a rota- evaporator under reduced pressure to give an oily mass which was diluted with water (500ml) and cooled to 10 - 150C to give a solid. The solid was filtered and washed with water and dried (50g, M.Pt. 70 - 720C.)
1H NMR (CDCl3): δ 7.26 - 7.23 (m, 4H), 7.14 - 7.11 (m, 4H), 5.77 (s, IH), 2.3 (s, 6H) Mass Spectrum: [M+ Na], 235
Example - 3
Preparation of α - (IH-I, 2,4-Triazolyl) - 4,4'-dimethyIdiphenyImethane (Ha)
A solution of 4,4'-dimethyl benzhydrol (25g, O.l lmol) in 1,2-dichloroethane (1000 ml) was cooled to -10 0C. and to it was added cone. Sulphuric acid (25 ml) drop-wise over a period of 30 minutes. The solution was stirred at this temperature for 30 min. more and added 1.2.4-triazole (25Og, 3,61 mol) in one lot. The reaction mixture was stirred for 3-
4h.
Unconsumed triazole was filtered out and the filtrate washed with (2x200ml) of water.
The organic layer was dried over Anh. Sodium Sulphate and then concentrated on a rota- evaporator to give alpha (IH-I, 2,4-Triazolyl) - 4,4'-dimethyldiphenylmethane (28g).
This was further purified by column chromatography (SiO2 60-120, Ethyl acetate: hexane). M.P. - 1010C.
IR (KBr) (v Cm"1): 1513.5, 1431.6 IH NMR (CDCl3): δ 8.0 (s, IH), 7.9 (s, IH)5 7.25 - 7.15 (m, 4H), 7.02 - 7.00 (m, 4H) 6.68 (s, IH), 2.34 (s, 12H). Mass Spectrum: [M+Na], 286
Example - 4
Preparation of α - (IH-I, 2,4-Triazolyl) - 4,4'-dimethylidinetetraacetoxy diphenyϊmethane (lib)
To a solution of alpha (IH-I, 2,4-Triazolyl) - 4,4'-dimethyldiphenylmethane (25g, 0.09 mol) in acetic anhydride (250ml) cooled to -15 °C, was added cone. Sulphuric acid (40 ml) over a period of 30 min. and stirred for another 30 min. at the same temperature. A solution of chromium trioxide (37.5g, 0.37 mol) in acetic anhydride (250 ml) was added to the reaction slowly at -15 -to -10°C in Ih.
The reaction mixture was further stirred for 4h The reaction mixture was poured into 2L of water and extracted with ethyl acetate (IL).
The ethyl acetate layer was dried and evaporated to give crude a - (IH-1, 2,4-Triazolyl) - 4,4'-dimethylidinetetraacetoxy diphenylmethane (4Og). This is on purification by column chromatography (SiO2, Ethyl acetate: Hexane) followed by recrystallisation from IPA produced the titled compound (12 g, M.Pt.lO3°C) . IR (KBr) (v Cm"1): 1753, 1515, 1424.5 1H NMR (CDCl3): δ 8.03 (s, IH), 7.97 (s, IH), 7.66 (s, 2H), 7.55 - 7.52 (m, 4H), 7.26 - 7.17 (m, 4H), 6.76 (s, IH), 2.12 (s, 12H). Mass Spectrum: [M+H]+ 496, [M+ Na]+ 518.1
Example - 5
Preparation of α - (IH-I, 2,4-Triazolyl) - 4,4'-diformyl diphenylmethane (lie)
To a solution of alpha (IH-I, 2,4-Triazolyl) - 4,4'-dimethylidinetetraacetoxy diphenylmethane (5g, 0.01 mol) in methanol (200 ml) was added a solution of potassium hydroxide (2.25g, 0.04 mol) dissolved in methanol (25 ml) at room temperature. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was neutralized with 6 N Hydrochloric acid. Methanol was removed under reduced pressure. Water (100 ml) was added to the residue and the products were extracted into ethyl acetate (100ml). Removal of ethyl acetate under reduced pressure gives crude alpha (IH- 1 , 2,4-Triazolyl) - 4,4'-diformyl diphenylmethane (2.8g).
This was further purified by column chromatography to give the pure product (Ig). IR (KBr) (v Cm4): 1703.8, 1605.8, 1503.5
1H NMR (CDCl3): δ 10.04 (s,2H), 8.08 (m, 2H3Tz), 7.93 - 7.91 (m, Ar, 4H), 7.36 - 7.27 (m,4H,Ar), 6.88 (s, IH)
Mass Spectrum: [M-I], 290.2
Example - 6 Preparation of α - (IH-1, 2,4-Triazolyl) - 4,4'-diformyI diphenylmethane (lie)
To a solution of alpha (IH-I, 2,4-Triazolyl) - 4,4'-dimethylidinetetraacetoxy diphenylmethane (5 g, 0.01 mol) in methanol (50 ml) was added Cone. HCl (5ml) at room temperature. The reaction mixture was refluxed for 2h. Methanol was removed under reduced pressure. Water (100 ml) was added to the residue and the products were extracted into ethyl acetate (100ml). Removal of ethyl acetate under reduced pressure gives crude alpha (IH-I, 2,4-Triazolyl) - 4,4'-diformyl diphenylmethane (2.5g).
This was further purified by column chromatography to give the pure product (1.6g). Example - 7
Preparation of α - (IH-I, 2,4-Triazolyl) - 4,4'-diformyl diphenylmethane (Hc)
To a solution of α - (IH-I, 2,4-Triazolyl) - 454'-dimethylidinetetraacetoxy diphenylmethane (5g, 0.01 mol) in isopropyl alcohol (50 ml) was added water (10ml) followed by Cone. Sulphuric acid (2ml) at room temperature. The reaction mixture was refluxed for 2h. Isopropyl alcohol was removed under reduced pressure. Water (100 ml) was added to the residue and the products were extracted into ethyl acetate (100ml).
Removal of ethyl acetate under reduced pressure gives crude α - (IH-I, 2,4-Triazolyl) - 4,4'-diformyl diphenylmethane (2.5g).
This was further purified by column chromatography to give the pure product (1.3g). Example - 8 Preparation of α - (IH-I, 2,4-Triazolyl) - 4,4'-diformaldoxime diphenylmethane (lid)
To a solution of α - (IH-I, 2,4-Triazolyl) - 4,4'-diformyl diphenylmethane (5g, 0.017 mol) in isopropyl alcohol (150 ml) was added a solution of hydroxy lamine hydrochloride (4.77g, 0.068 mol) in water (30ml) previously neutralized with potassium hydroxide (3.84g, 0.068 mol) at room temperature. The reaction mixture was refluxed for 4hrs. Isopropyl alcohol was removed on a rota-evaporator under reduced pressure to leave a gummy mass. Water (50ml) was added to the residue and stirred for 2-3h at 10 0C. The solid mass separated was filtered and dried (4.13g). M.Pt. 222 - 224 °C. A sample of the product was further recrystallised from methanol to give the pure compound, m. p. 234.6° C.
IR (KBr) (v CIΏ 1): 3270, 2970, 1510, and 1450
1H NMR (DMSO-d6): δ ppm 11.3 (s,2H), 8.12 (s, IH), 8.08 (s, IH), 7.61 - 7.58 (m, 4H), 7.26 - 7.24 (m,4H), 7.13 (s, IH), Mass Spectrum: [M+H]+, 322.1 , [M+ Na]+, 344.1 , [M- Triazole+ H]+, 254.2 Example - 9
Preparation of α- (IH-1, 2,4-Triazolyl) - 4,4'-diformaIdoxime diphenylmethane (lid) To a solution of alpha (IH-I, 2,4-Triazolyl) - 4,4'-dimethylidinetetraacetoxy diphenylmethane (5g, 0.01 mol) in isopropyl alcohol (100 ml) was added a solution of hydroxylamine hydrochloride (2.8g, 0.04 mol) in water (10ml) previously neutralized with potassium hydroxide (2.25g, 0.04 mol) at room temperature. The reaction mixture was refluxed for 4hrs. Isopropyl alcohol was removed on a rota evaporator under reduced pressure to leave a gummy mass. Water (50ml) was added to the residue and stirred for 2- 3h at 10 0C. The solid mass thus separated was filtered and dried (2.5g). Example - 10
Preparation of 4,4'-(1H-I, 2,4-triazol-lyl-methylene)-bisbenzonitrile / Letrozole (I)
A solution of alpha (IH-I, 2,4-Triazolyl) - 4,4'-diformaldoxime diphenylmethane (5g,
0.015 mol) in acetic anhydride (12.5ml) was refluxed for 8-1Oh. The reaction mixture was cooled to room temperature and poured into water (200ml) and stirred for Ih. The solid mass precipitated was filtered. The residue was washed several times with water to remove acetic anhydride. The solid was dried to get Letrozole (4.3g).
1H NMR (CDCl3): δ ppm 8.09 (s, IH), 8.07 (s, IH), 7.72 - 7.69 (m, 4H), 7.36 - 7.27 (m, 4H), 6.84 (s, IH), Mass Spectrum: [M-I], 284.3 Example - 11
Preparation of 4,4'-(1H-I, 2,4-triazol-lyl-methylene)-bisbenzonitrile / Letrozole (I)
To a suspension of α -(1H-I, 2,4-Triazolyl) - 4,4'-diformaldoxime diphenylmethane (5g, 0.015 mol) in acetic acid (75 ml) was added acetic anhydride (7.35 ml) and sodium acetate (6.38 g, 0.77 mol) at room temperature. The mixture was then refluxed for 3-4h.
The reaction mixture was cooled to room temperature and poured into water (400ml) at room temperature and stirred for Ih. The solid mass precipitated was filtered. The residue was washed several times with water to remove acetic anhydride. The solid was dried to give Letrozole (4.6g).

Claims

1. A compound of formula II,
Figure imgf000021_0001
wherein R1 and R2 are same and are selected from methyl, CH (OCOCH3) 2, CHO or CH=N-OH and salts thereof.
2. A compound of formula (Ha)
Figure imgf000021_0002
3. A compound of formula (lib)
Figure imgf000021_0003
4. A compound of formula (lie)
Figure imgf000022_0001
5. A compound of formula (Hd)
Figure imgf000022_0002
6. A process for preparation of Letrozole of formula (I),
Figure imgf000022_0003
comprising the steps of: a. reacting 4,4-Dimethyl benzhydrol (9), with (lH)-l,2,4-triazole (2)
Figure imgf000022_0004
with (IH) 1,2,4-triazole (2) in presence of a halogenated hydrocarbon and an acid to give compound of formula (Ha);
Figure imgf000023_0001
b. if desired, effecting oxidation of compound of formula (Ha) with an oxidizing agent in the presence of acetic anhydride and a mineral acid to give compound of formula (lib);
Figure imgf000023_0002
if desired treating the compound of formula (lib) with a solution of an alkali metal hydroxide in an alcohol or with a solution of a mineral acid in an alcohol to give compound of formula (lie);
(Hc)
Figure imgf000023_0003
d. if desired reacting the compound of formula (lie) with hydroxylamine hydrochloride in an alcoholic solvent to give compound of formula (Hd); and
Figure imgf000024_0001
e. if desired reacting the compound of formula (lid) with acetic anhydride and sodium acetate in acetic acid to give Letrozole of formula (I).
Figure imgf000024_0002
7. A process according to claim 6, wherein the halogenated hydrocarbon of Step (a) is selected from dichloromethane, dichloroethane, carbon tetrachloride and chloroform.
8. A process according claim 7, wherein the halogenated hydrocarbon is 1,2- dichloroethane.
9. A process according to claim 6, wherein the acid of step (a) is selected from HCl, H2SO4, H3PO4, and HNO3.
10. A process according to claim 6, wherein the oxidizing agent of Step (b) is selected from chromyl chloride, chromyl acetate, and chromium trioxide.
11. A process according to claim 6, wherein the alkali metal hydroxide of Step (c) is selected from a lithium hydroxide, sodium hydroxide, and potassium hydroxide.
12. A process according to claim 6, wherein the mineral acid of steps (b) and (c) is selected from HCl, H2SO4, H3PO4, and HNO3.
13. A process according to claim 6, wherein the alcohol of steps (c) and (d) is selected from methanol, ethanol and isopropanol.
14. A process for preparation of Letrozole of formula (I),
Figure imgf000025_0001
comprising the steps of: a. reacting 4,4-Dimethyl benzhydrol (9), with (lH)-l,2,4-triazole (2)
Figure imgf000025_0002
in presence of a halogenated hydrocarbon and an acid to give compound of formula (Ha);
(Ha)
Figure imgf000025_0003
b. if desired, effecting oxidation of compound of formula (Ha) with an oxidizing agent in the presence of acetic anhydride and a mineral acid to give compound of formula (lib);
Figure imgf000026_0001
c. if desired, reacting the compound of formula (lib) with hydroxylamine hydrochloride in an alcoholic solvent to give compound of formula (Hd); and
Figure imgf000026_0002
d. if desired, reacting the compound of formula (Hd) with acetic anhydride and sodium acetate in acetic acid to give Letrozole of formula (I).
Figure imgf000026_0003
15. A process according to claim 14, wherein the halogenated hydrocarbon of Step (a) is selected from dichloromethane, dichloroethane, carbon tetrachloride and chloroform.
16. A process according to claim 15, wherein the halogenated hydrocarbon is 1,2- dichloroethane.
17. A process according to claim 14, wherein the acid of step (a) is selected from HCl, H2SO4, H3PO4, and HNO3.
18. A process according to claim 14, wherein the oxidizing agent of Step (b) is selected from chromyl chloride, chromyl acetate, and chromium trioxide.
19. A process according to claim 14, wherein the mineral acid of step (b) is selected from HCl, H2SO4, H3PO4, and HNO3. '
20. A process according to claim 14, wherein the alcohol of step (c) is selected from methanol, ethanol and isopropanol.
PCT/IN2006/000491 2005-12-27 2006-12-13 Novel intermediates for preparation of letrozole WO2007074474A1 (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7705159B2 (en) 2005-07-06 2010-04-27 Sicor, Inc. Process for the preparation of letrozole
US8198460B2 (en) 2007-11-28 2012-06-12 Fresenius Kabi Oncology Ltd. Process for preparation of letrozole and its intermediates
CN103435563A (en) * 2013-08-22 2013-12-11 江苏苏南药业实业有限公司 Method for preparing letrozole
CN103664810A (en) * 2013-12-11 2014-03-26 深圳劲创生物技术有限公司 Process for synthesizing letrozole

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5473078A (en) * 1986-03-07 1995-12-05 Ciba-Geigy Corporation Alpha-heterocycle substituted tolunitriles
US20050209294A1 (en) * 2004-03-17 2005-09-22 Wadhwa Lalit K Process for producing 4-(1H-1,2,4-triazol-1-ylmethyl)benzonitrile

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5473078A (en) * 1986-03-07 1995-12-05 Ciba-Geigy Corporation Alpha-heterocycle substituted tolunitriles
US20050209294A1 (en) * 2004-03-17 2005-09-22 Wadhwa Lalit K Process for producing 4-(1H-1,2,4-triazol-1-ylmethyl)benzonitrile

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
J. MARCH: "Advanced organic chemistry; third edition", 1985, JOHN WILEY & SONS, XP002427280 *
KATRITZKY ET AL.: "Novel heterocyclic analogs of trityl radicals: synthesis and dimerization of diarylmethyl-1H-1,2,4-triazoles and diarylmethyl-2H-phenanthro[9,10-d]-1,2,3-triazoles", HETEROCYCLES, vol. 52, no. 1, 2000, pages 203 - 214, XP001245675 *
WANG E-C ET AL: "A New One Pot Method for the Conversion of Aldehydes into Nitriles Using Hydroxyamine and Phthalic Anhydride", 4 June 1998, TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, NL, PAGE(S) 4047-4050, ISSN: 0040-4039, XP004118808 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7705159B2 (en) 2005-07-06 2010-04-27 Sicor, Inc. Process for the preparation of letrozole
US8198460B2 (en) 2007-11-28 2012-06-12 Fresenius Kabi Oncology Ltd. Process for preparation of letrozole and its intermediates
CN103435563A (en) * 2013-08-22 2013-12-11 江苏苏南药业实业有限公司 Method for preparing letrozole
CN103664810A (en) * 2013-12-11 2014-03-26 深圳劲创生物技术有限公司 Process for synthesizing letrozole
CN103664810B (en) * 2013-12-11 2016-09-14 深圳劲创生物技术有限公司 A kind of technique synthesizing letrozole

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