+

WO2007039912A1 - A one pot process for the preparation of 4-[1-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile - Google Patents

A one pot process for the preparation of 4-[1-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile Download PDF

Info

Publication number
WO2007039912A1
WO2007039912A1 PCT/IN2005/000331 IN2005000331W WO2007039912A1 WO 2007039912 A1 WO2007039912 A1 WO 2007039912A1 IN 2005000331 W IN2005000331 W IN 2005000331W WO 2007039912 A1 WO2007039912 A1 WO 2007039912A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
methyl
organic solvent
benzonitrile
Prior art date
Application number
PCT/IN2005/000331
Other languages
French (fr)
Inventor
Venkatasubramanian Radhakrishnan Tarur
Nandu Baban Bhise
Dhananjay Govind Sathe
Chhayendra Janardan Chaudhari
Mehul Ashokkumar Joshi
Original Assignee
Usv Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Usv Limited filed Critical Usv Limited
Priority to PCT/IN2005/000331 priority Critical patent/WO2007039912A1/en
Publication of WO2007039912A1 publication Critical patent/WO2007039912A1/en

Links

Classifications

    • 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 a one pot process for the preparation of highly pure 4-[l- cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile of the formula (I):
  • the present invention also relates to highly pure 4-[l-cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile of the formula (I) prepared by the above process.
  • Letrozole 4-[l-cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile, commonly known as Letrozole, is an antineoplastic agent. Letrozole is an aromatase inhibitor which prevents formation of estrogen. Although estrogen is a hormone naturally produced by the body, it can stimulate and maintain the growth of certain types of cancer. Letrozole slows or stops the growth of cancer cells by decreasing the amount of estrogen produced and is used to treat advanced breast cancer in postmenopausal women with disease progression after antiestrogen therapy.
  • the compound of the formula (IV) is treated with 4-fluorobenzonitrile of the formula (V) in the presence of potassium tertiary butoxide as a catalyst in N,N-dimethylformamide below 5° C to obtain 4-[l-(4-cyanophenyl)-l-(l,2,4-triazol-l-yl)methyl]benzonitrile of the formula (I).
  • the reaction scheme is as illustrated below:
  • the process uses a mixture of solvents comprising chloroform and acetonitrile to carry out the condensation of ⁇ -Bromotolunitrile with 1,2,4-triazole. Recovery of the solvent mixture is difficult from the reaction mixture and thus cannot be recycled at industrial scale.
  • the time required for the preparation of 4-[l-(l,2,4-triazol-l-yl)methyl]benzonitrile of the formula (IV) is reported to be more than 15 hour.
  • the patent does not mention the purity and yield of 4-[l-(l,2,4- triazol-l-yl)methyl]benzonitrile of the formula (IV).
  • the yield of the compound of the formula (IV) was found to be 20 to 25 %. It was also found to contain undesired isomer of the formula (VI):
  • WO 2004/076409 describes a regiospecific preparation of 4-[l-cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile of the formula (I), substantially free of isomeric impurities of the formulae (VI) and (VII).
  • This process uses protected triazole, to reduce isomeric impurity of the formula (VI) thereby requiring an additional step of deprotection of the compound of the formula (VIII) to obtain 4-[l- (l,2,4-triazol-l-yl)methyl]benzonitrile of the formula (IV). Moreover deprotection with hydrochloric acid and sodium nitrite leads to formation of toxic nitrous acid. If the starting material, oc-halotolunitrile of the formula (II) contains an impurity like 4-toluonitrile the reaction with 4-fluorobenzonitrile may lead to the formation of 4-[l,l-bis(4- cyanophenyl)methyl]benzonitrile (IX) which is undesirable.
  • An object of the present invention is to provide a one pot process for the preparation of 4-[l- cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile of the formula (I) in high yield and in high purity.
  • Another object of the invention is to provide a cost effective, simple, economical and industrially feasible process for the preparation of highly pure 4-[l-cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile of the formula (I) in high yield.
  • Another object of the present invention is to provide process for the preparation of highly pure 4- [l-cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile of the formula (I) in high yield which reduces the process time.
  • Another object of the invention is to provide highly pure 4-[l-cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile of the formula (I) in high yield prepared by the above process.
  • the alkali metal salts of 1,2,4-triazole of the formula (DI b) used in step (a) are sodium or potassium salts.
  • the organic solvent used in step (a) is selected from dipolar aprotic solvent such as dimethylsulphoxide, dimethylacetamide, 1,2-dimethoxy/diethoxyethane or dimethylformamide; halo substituted or unsubstituted alkyl and aryl hydrocarbons such as hexane, toluene, xylene, methylene chloride, chloroform or dichloroethane; ketones such as acetone, methylisobutyl ketone or methylethylketone; nitriles such as acetonitrile; esters such as ethyl acetate; ethers such as diphenylether or diisopropylether; or alcohols such as ethanol, methanol, isopropanol or t-butanol or
  • the organic solvent used in step (a) is N,N-dimethylformamide or N,N-dimethylacetamide.
  • the condensation of the compound of the formula (II) with 1,2,4- triazole of the formula (in b) is carried out at temperature 40 to 70° C.
  • the base used in step (b) is selected from organic or inorganic base. More preferably the base used in step (b) is n-butyl lithium, sodium tertiary butoxide, potassium tertiary butoxide, potassium or sodium isopropoxide, potassium or sodium ethoxide, potassium or sodium methoxide, sodium hydride, lithium hydride or diisopropyl ethyl amine.
  • the compound of the formula (I) is isolated from the reaction mixture by extracting the reaction mixture with organic solvent selected from ethyl acetate, dichloromethane or chloroform.
  • the organic solvent used in recrystallization of the compound of the formula (I) in step (d) or (d 1 ) is selected from toluene, xylene, methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, iso-propyl acetate, petroleum ethers, hexane or water or mixtures thereof.
  • the recrystallization of the compound of the formula (I) in step (d) or (d 1 ) is carried out in solvent selected from ethanol or mixture of ethanol-hexane or ethanol-diethyl ether.
  • the stationary phase of the column chromatography used to purify the compound of the formula (I) is selected from silica gel or alumina.
  • the stationary phase of the column chromatography used to purify the compound of the formula (I) is the silica gel having particle size between 60-120 mesh.
  • the mobile phase of the column chromatography used to purify the compound of the formula (I) is selected from aliphatic or aromatic hydrocarbons; alcohols; ketones or aliphatic solvents such as esters, nitriles; halogeneted solvent or mixtures thereof.
  • the mobile phase of the column chromatography used to purify the compound of the formula (I) is mixture of ethylacetate-hexane or mixture of dichloroniethane-acetonitrile.
  • the process of the invention provides Letrozole of the formula (I) in high yield (about 40 to 60 %) and in high purity (> 99.6 %) in a one pot reaction without isolating the intermediate, 4-[l-( 1,2,4- triazol-l-yl)methyl]benzonitrile. It uses a single solvent, which is easily recovered and recycled into the subsequent batch.
  • the impurities level is reduced to 0.4% constituted mainly by 4-[l,l- bis(4-cyanophenyl)methyl]benzonitrile of the formula (IX) and 4-[l-(4-cyanophenyl)-l-(l,2,4- triazol-4-yl)methyl]benzonitrile of the formula (VII).
  • Example 1 oc-Bromotolunitrile (10 g, 0.051 moles) was heated with a sodium salt of 1,2,4-triazole (6.3 g, 0.068 moles) in N,N-dimethylformamide (50 ml) for 2hour at 40°C. The reaction mixture was cooled at -5°C and potassium tertiary butoxide (14.3 g, 0.127 moles) was added in small portions for 30 min. The reaction mixture was stirred at 0 to 5°C for 2 hour. To this reaction mixture, 4- fluorobenzonitrile (6.5 g, 0.053 moles) was added in 30 min at -5 to 0 0 C and stirred at 0 to 5°C for 2 hour. The reaction mixture was poured into cooled 2N hydrochloric acid and extracted with ethyl acetate. An organic layer was washed with water and concentrated under vacuum to yellow solid.
  • 1,2,4-triazole 6.3 g, 0.068 moles
  • Example 2 oc-Bromotolunitrile (10 g, 0.051 moles) was heated with a sodium salt of 1,2,4-triazole (6.3 g, 0.068 moles) in N,N-dimethylformamide (50 ml) for 2 hour at 4O 0 C. The reaction mixture was cooled at - 5°C and potassium tertiary butoxide (14.31 g, 0.127 moles) was added in small portions for 30 min. The reaction mixture was stirred at 0 to 5°C for 2 hour. To this reaction mixture, 4-fluorobenzonitrile (6.49 g, 0.053 moles) was added in 30 min at -5 to 0 0 C and stirred at 0 to 5 0 C for 2 hour. The reaction mixture was poured into cooled 2N hydrochloric acid and extracted with ethyl acetate. An organic layer was washed with water and concentrated under vacuum to yellow solid.
  • 1,2,4-triazole 6.3 g, 0.068 moles
  • the crude Letrozole was purified by column chromatography using 20-50% ethylacetate in hexane as an eluent.
  • the solid obtained was recystallized from ethanol-hexane (250 ml and 25 ml) mixture.
  • the structure was confirmed by IH NMR, IR and mass spectral analysis.
  • Example 3 oc-Bromotolunitrile (1O g, 0.051 moles) was heated with a sodium salt of 1,2,4-triazole (6.3 g, 0.068 moles) in N,N-dimethylformamide (50 mL) for 2 hour at 40°C. The reaction mixture was cooled at -5°C and potassium tertiary butoxide (14.31 g, 0.127 moles) was added in small portion for 30 min. The reaction mixture was stirred at 0 to 5 0 C for 2 hour. To this reaction mixture, A- fluorobenzonitrile (6.49 g, 0.053 moles) was added in 30 min at -5 to O 0 C and stirred at 0 to 5°C for 2 hour. The reaction mixture was poured into cooled 2N hydrochloric acid and extracted with ethyl acetate. An organic layer was washed with water and concentrated under vacuum to yellow solid.
  • 1,2,4-triazole 6.3 g, 0.068 moles
  • the crude was purified by column chromatography using 3 to 10 % acetonitrile in dichloromethane as an eluent.
  • the solid obtained was recystallized from alcohol.
  • the structure was confirmed by IH NMR, IR and mass spectral analysis.

Landscapes

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

Abstract

The invention discloses a one pot process for the preparation of highly pure 4-[l-cyanophenyl)-l- (1,2,4-triazol-l-yl) methyl] benzonitrile (Letrozole) without isolation of the intermediate 4-[l- (l,2,4-triazol-l-yl)methyl]benzonitrile. oc-Bromotolunitrile is condensed with alkali metal salt of 1 ,2,4-triazole in an organic solvent. 4-Fluorobenzonitrile is charged into the condensate in the presence of a base to give crude Letrozole which is purified by recrystallization alone or in combination with column chromatography.

Description

A one pot process for the preparation of 4-[l-cyanophenyl)-l-(l,2,4- triazol-l-yl)methyl] benzonitrile
Technical Field The present invention relates to a one pot process for the preparation of highly pure 4-[l- cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile of the formula (I):
Figure imgf000002_0001
Formula (I) The present invention also relates to highly pure 4-[l-cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile of the formula (I) prepared by the above process.
4-[l-cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile, commonly known as Letrozole, is an antineoplastic agent. Letrozole is an aromatase inhibitor which prevents formation of estrogen. Although estrogen is a hormone naturally produced by the body, it can stimulate and maintain the growth of certain types of cancer. Letrozole slows or stops the growth of cancer cells by decreasing the amount of estrogen produced and is used to treat advanced breast cancer in postmenopausal women with disease progression after antiestrogen therapy.
BACKGROUND OF THE INVENTION
US 4,978,672 reports Letrozole and also describes a process for its preparation, α- Bromotolunitrile of the formula (II) is condensed with 1,2,4-triazole of the formula (III) in a mixture of chloroform and acetontrile at reflux temperature for 15 hour to obtain 4-[l-(l,2,4- triazol-l-yl)methyl]benzonitrile of the formula (IV), which is purified by column chromatography using silica gel as stationary phase and chloroform and isopropanol (10: 1) as eluent. The compound of the formula (IV) is treated with 4-fluorobenzonitrile of the formula (V) in the presence of potassium tertiary butoxide as a catalyst in N,N-dimethylformamide below 5° C to obtain 4-[l-(4-cyanophenyl)-l-(l,2,4-triazol-l-yl)methyl]benzonitrile of the formula (I). The reaction scheme is as illustrated below:
Figure imgf000003_0001
(III) (IV) wherein X : Cl or Br or I
Figure imgf000003_0003
Figure imgf000003_0002
(IV) (V) ©
The process uses a mixture of solvents comprising chloroform and acetonitrile to carry out the condensation of α-Bromotolunitrile with 1,2,4-triazole. Recovery of the solvent mixture is difficult from the reaction mixture and thus cannot be recycled at industrial scale. The time required for the preparation of 4-[l-(l,2,4-triazol-l-yl)methyl]benzonitrile of the formula (IV) is reported to be more than 15 hour. The patent does not mention the purity and yield of 4-[l-(l,2,4- triazol-l-yl)methyl]benzonitrile of the formula (IV). On carrying out the same procedure in our laboratory the yield of the compound of the formula (IV) was found to be 20 to 25 %. It was also found to contain undesired isomer of the formula (VI):
Figure imgf000003_0004
Formula (VI)
If the compound of the formula (IV) is not purified to eliminate the undesired isomer of the formula (VI) then the 4-[l-cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile of the compound of the formula (I) is found to contain isomer of the formula (VII), which is also undesirable.
Figure imgf000004_0001
Formula (VII)
Purification of the crude product, 4-[l-(l,2,4-triazol-l-yl)methyl]benzonitrile (IV) is carried out by column chromatography, which makes the process tedious and time consuming which increases the solvent requirement of the process. Therefore, the process is not industrially and commercially viable and economical. This patent does not also disclose the purity of 4-[l- cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile of the formula (I).
WO 2004/076409 describes a regiospecific preparation of 4-[l-cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile of the formula (I), substantially free of isomeric impurities of the formulae (VI) and (VII). 4-Brpmomethylbenzonitrile of the formula (II) is reacted with 4-amino- 1,2,4- triazole of the formula (III a) to give 4-[4-amino-l,2,4-triazolium-l-yl)methyl] benzonitrile bromide of the formula (VIII) followed by deamination by treatment with concentrated hydrochloric acid and sodium nitrite to yield the compound of the formula (IV) substantially free of isomeric impurities. The compound of the formula (IV) is further reacted with 4- fluorobenzonitrile of the formula (V) to obtain Letrozole of the formula (I) substantially free of isomeric impurities of the formula (VII). The reaction scheme is as illustrated below;
Figure imgf000005_0001
Figure imgf000005_0002
(VIII) αv)
Figure imgf000005_0003
αv) (V) CO
This process uses protected triazole, to reduce isomeric impurity of the formula (VI) thereby requiring an additional step of deprotection of the compound of the formula (VIII) to obtain 4-[l- (l,2,4-triazol-l-yl)methyl]benzonitrile of the formula (IV). Moreover deprotection with hydrochloric acid and sodium nitrite leads to formation of toxic nitrous acid. If the starting material, oc-halotolunitrile of the formula (II) contains an impurity like 4-toluonitrile the reaction with 4-fluorobenzonitrile may lead to the formation of 4-[l,l-bis(4- cyanophenyl)methyl]benzonitrile (IX) which is undesirable.
Figure imgf000005_0004
Formula (IX) OBJECTS OF THE INVENTION:
An object of the present invention is to provide a one pot process for the preparation of 4-[l- cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile of the formula (I) in high yield and in high purity.
Another object of the invention is to provide a cost effective, simple, economical and industrially feasible process for the preparation of highly pure 4-[l-cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile of the formula (I) in high yield.
Another object of the present invention is to provide process for the preparation of highly pure 4- [l-cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile of the formula (I) in high yield which reduces the process time.
Another object of the invention is to provide highly pure 4-[l-cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile of the formula (I) in high yield prepared by the above process.
DETAILED DESCRIPTION OF THE INVENTION
According to the invention there is provided a one pot process for preparation of 4-[l- cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile of the formula (I):
Figure imgf000006_0001
Formula (I) the process comprising a. condensing 4-halomethyl benzonitrile of the formula (II)
Figure imgf000007_0001
wherein X = Cl or Br or I Formula (II)
with alkali metal salts of 1,2,4-triazole of the formula (III b)
Figure imgf000007_0002
wherein M+ : Na+ / K+
Formula (III b) in an organic solvent at temperature of 40 to 100° C; b. charging 4-fluorobenzonitrile of the formula (V)
Figure imgf000007_0003
Formula (V) to the condensate in the presence of a base at temperature of - 5 to 5° C to obtain crude 4-[l-cyanophenyl)-l-(l,2,4-triazol-l-yi) methyl] benzonitrile of.the formula (I); and c. isolating the crude compound of the formula (I) by extracting the reaction mixture with an organic solvent followed by distillation of the solvent under vacuum; and d. purifying the compound of the formula (I) by recrystallization using an organic solvent. According to the invention there is also provided a one pot process for preparation of 4-[l- cyanoρhenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile of the formula (I):
Figure imgf000008_0001
Formula (I) the process comprising a. condensing 4-halomethyl benzonitrile of the formula (II)
Figure imgf000008_0002
wherein X = Cl or Br or I
Formula (H) with alkali metal salts of 1 ,2,4-triazole of the formula (HI b)
Figure imgf000008_0003
wherein M+ : Na+ / K+
Formula (EI b) in an organic solvent at temperature of 40 to 100° C; b. charging 4-fluorobenzonitrile of the formula (V)
Figure imgf000008_0004
Formula (V) to the condensate in the presence of a base at temperature of - 5 to 5° C to obtain crude 4-[l-cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile of the formula
(I); c. isolating the crude compound of the formula (I) by extracting the reaction mixture with an organic solvent followed by distillation of the solvent under vacuum; and d1 purifying the compound of the formula (I) by column chromatography using a stationary phase and a mobile phase followed by recrystallization using an organic solvent.
Preferably the alkali metal salts of 1,2,4-triazole of the formula (DI b) used in step (a) are sodium or potassium salts. Preferably the organic solvent used in step (a) is selected from dipolar aprotic solvent such as dimethylsulphoxide, dimethylacetamide, 1,2-dimethoxy/diethoxyethane or dimethylformamide; halo substituted or unsubstituted alkyl and aryl hydrocarbons such as hexane, toluene, xylene, methylene chloride, chloroform or dichloroethane; ketones such as acetone, methylisobutyl ketone or methylethylketone; nitriles such as acetonitrile; esters such as ethyl acetate; ethers such as diphenylether or diisopropylether; or alcohols such as ethanol, methanol, isopropanol or t-butanol or mixtures thereof. More preferably the organic solvent used in step (a) is N,N-dimethylformamide or N,N-dimethylacetamide. Preferably the condensation of the compound of the formula (II) with 1,2,4- triazole of the formula (in b) is carried out at temperature 40 to 70° C.
Preferably the base used in step (b) is selected from organic or inorganic base. More preferably the base used in step (b) is n-butyl lithium, sodium tertiary butoxide, potassium tertiary butoxide, potassium or sodium isopropoxide, potassium or sodium ethoxide, potassium or sodium methoxide, sodium hydride, lithium hydride or diisopropyl ethyl amine. Preferably the compound of the formula (I) is isolated from the reaction mixture by extracting the reaction mixture with organic solvent selected from ethyl acetate, dichloromethane or chloroform.
The organic solvent used in recrystallization of the compound of the formula (I) in step (d) or (d1) is selected from toluene, xylene, methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, iso-propyl acetate, petroleum ethers, hexane or water or mixtures thereof. Preferably the recrystallization of the compound of the formula (I) in step (d) or (d1) is carried out in solvent selected from ethanol or mixture of ethanol-hexane or ethanol-diethyl ether. The stationary phase of the column chromatography used to purify the compound of the formula (I) is selected from silica gel or alumina. Preferably the stationary phase of the column chromatography used to purify the compound of the formula (I) is the silica gel having particle size between 60-120 mesh. The mobile phase of the column chromatography used to purify the compound of the formula (I) is selected from aliphatic or aromatic hydrocarbons; alcohols; ketones or aliphatic solvents such as esters, nitriles; halogeneted solvent or mixtures thereof. Preferably the mobile phase of the column chromatography used to purify the compound of the formula (I) is mixture of ethylacetate-hexane or mixture of dichloroniethane-acetonitrile.
The process of the invention provides Letrozole of the formula (I) in high yield (about 40 to 60 %) and in high purity (> 99.6 %) in a one pot reaction without isolating the intermediate, 4-[l-( 1,2,4- triazol-l-yl)methyl]benzonitrile. It uses a single solvent, which is easily recovered and recycled into the subsequent batch. The impurities level is reduced to 0.4% constituted mainly by 4-[l,l- bis(4-cyanophenyl)methyl]benzonitrile of the formula (IX) and 4-[l-(4-cyanophenyl)-l-(l,2,4- triazol-4-yl)methyl]benzonitrile of the formula (VII).
Figure imgf000010_0002
Figure imgf000010_0001
Formula (VII)
Use of alkali metal salts of 1,2,4-triazole of the formula (III b) in the condensation reaction helps to improve the reaction rate and the process duration is also reduced to the order of 5 to 10 hours. The process is a cost effective, simple, economical and industrially feasible. The process of the present invention is described by the following examples, which are illustrations only and not to be considered to limit to the scope of the invention in any manner.
Example 1 oc-Bromotolunitrile (10 g, 0.051 moles) was heated with a sodium salt of 1,2,4-triazole (6.3 g, 0.068 moles) in N,N-dimethylformamide (50 ml) for 2hour at 40°C. The reaction mixture was cooled at -5°C and potassium tertiary butoxide (14.3 g, 0.127 moles) was added in small portions for 30 min. The reaction mixture was stirred at 0 to 5°C for 2 hour. To this reaction mixture, 4- fluorobenzonitrile (6.5 g, 0.053 moles) was added in 30 min at -5 to 00C and stirred at 0 to 5°C for 2 hour. The reaction mixture was poured into cooled 2N hydrochloric acid and extracted with ethyl acetate. An organic layer was washed with water and concentrated under vacuum to yellow solid.
[Yield of crude Letrozole: 12.30 g (85%); Purity: 90% (HPLC)].
The crude solid of Letrozole was recrystallized from ethanol to give pure 4-[l-cyanophenyl)-l- (1,2,4-triazol-l-yl) methyl] benzonitrile (Letrozole). The structure was confirmed by IH NMR, IR and mass spectral analysis.
[Yield of Pure Letrozole: 6.98 g, 40%; Purity: >99.6% (HPLC) and M.P.: 181-183 0C].
Example 2 oc-Bromotolunitrile (10 g, 0.051 moles) was heated with a sodium salt of 1,2,4-triazole (6.3 g, 0.068 moles) in N,N-dimethylformamide (50 ml) for 2 hour at 4O0C. The reaction mixture was cooled at - 5°C and potassium tertiary butoxide (14.31 g, 0.127 moles) was added in small portions for 30 min. The reaction mixture was stirred at 0 to 5°C for 2 hour. To this reaction mixture, 4-fluorobenzonitrile (6.49 g, 0.053 moles) was added in 30 min at -5 to 00C and stirred at 0 to 50C for 2 hour. The reaction mixture was poured into cooled 2N hydrochloric acid and extracted with ethyl acetate. An organic layer was washed with water and concentrated under vacuum to yellow solid.
[Yield of crude Letrozole : 12.4 g, 85%; Purity: 90% (HPLC)].
The crude Letrozole was purified by column chromatography using 20-50% ethylacetate in hexane as an eluent. The solid obtained was recystallized from ethanol-hexane (250 ml and 25 ml) mixture. The structure was confirmed by IH NMR, IR and mass spectral analysis.
[Yield of pure Letrozole : 8.73 g, 60%; Purity: >99.6% (HPLC) and M.P. 181-183 0C].
Example 3 oc-Bromotolunitrile (1O g, 0.051 moles) was heated with a sodium salt of 1,2,4-triazole (6.3 g, 0.068 moles) in N,N-dimethylformamide (50 mL) for 2 hour at 40°C. The reaction mixture was cooled at -5°C and potassium tertiary butoxide (14.31 g, 0.127 moles) was added in small portion for 30 min. The reaction mixture was stirred at 0 to 50C for 2 hour. To this reaction mixture, A- fluorobenzonitrile (6.49 g, 0.053 moles) was added in 30 min at -5 to O0C and stirred at 0 to 5°C for 2 hour. The reaction mixture was poured into cooled 2N hydrochloric acid and extracted with ethyl acetate. An organic layer was washed with water and concentrated under vacuum to yellow solid.
[Yield of crude Letrozole : 12.4 g, 85%; Purity: 90% (HPLC)].
The crude was purified by column chromatography using 3 to 10 % acetonitrile in dichloromethane as an eluent. The solid obtained was recystallized from alcohol. The structure was confirmed by IH NMR, IR and mass spectral analysis.
[Yield of pure Letrozole : 8.73 g, 55%; Purity: >99.97% (HPLC) and M.P. 181-183 0C].

Claims

1. A one pot process for preparation of 4-[l-cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile of the formula (I):
Figure imgf000013_0001
Formula (J) the process comprising a. condensing 4-halomethyl benzonitrile of the formula (H)
Figure imgf000013_0002
wherein X = Cl or Br or I Formula (II)
with alkali metal salts of 1,2,4-triazole of the formula (HI b)
Figure imgf000013_0003
wherein M+ : Na+ / K+
Formula (JH b) in an organic solvent at temperature of 40 to 100° C; b. charging 4-fluorobenzonitrile of the formula (V)
Figure imgf000014_0001
Formula (V) to the condensate in the presence of a base at temperature of - 5 to 5 ° C to obtain crude 4-[l-cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile of the formula (I); and c. isolating the crude compound of the formula (I) by extracting the reaction mixture with an organic solvent followed by distillation of the solvent under vacuum; and d. purifying the compound of the formula (I) by recrystallization using an organic solvent.
2. The process as claimed in claim 1, wherein the alkali metal salts of 1,2,4-triazole of the formula (JH b) used in step (a) are sodium or potassium salts.
3. The process as claimed in claim 1, wherein the organic solvent used in step (a) is selected from dipolar aprotic solvent such as dimethylsulphoxide, dimethylacetamide, 1,2- dimethoxy/diethoxyethane or dimethylformamide; halo substituted or unsubstituted alkyl and aryl hydrocarbons such as hexane, toluene, xylene, methylene chloride or dichloroethane; ketones such as acetone, methylisobutyl ketone or methylethylketone; nitriles such as acetonitrile; esters such as ethyl acetate; ethers such as diphenylether or diisopropyl ether; or alcohols such as ethanol, methanol, isopropanol or tert-butanol or mixtures thereof.
4. The process as claimed in claim 1, wherein the organic solvent used in step (a) is N,N- dimethylformamide or N,N-dimethylacetamide.
5. The process as claimed in claim 1, wherein the condensation of the compound of the formula (It) with 1,2,4- triazole of the formula (DI b) is carried out at temperature 40 to 7O0 C.
6. The process as claimed in claim 1, wherein the base used in step (b) is selected from organic base or inorganic base.
7. The process as claimed in claim 1, wherein the base used in step (b) is n-butyl lithium, sodium tertiary butoxide, potassium tertiary butoxide, potassium or sodium isopropoxide, potassium or sodium ethoxide, potassium or sodium methoxide, sodium hydride, lithium hydride, calcium hydride, triethylamine or diisopropyl ethyl amine.
8. The process as claimed in claim 1, wherein the compound of the formula (I) is isolated from the reaction mixture by extracting the reaction mixture with organic solvent selected from ethyl acetate, dichloromethane or chloroform.
9. The process as claimed in claim 1, wherein the organic solvent used in recrystallization of the compound of the formula (I) in step (d) is selected from toluene, xylene, methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, iso-propyl acetate, petroleum ethers, hexane or water or mixtures thereof.
10. The process as claimed in claim 1, wherein the recrystallization of the compound of the formula (I) in step (d) is carried out in a solvent selected from ethanol or mixture of ethanol-hexane.
11. A one pot process for preparation of 4-[l-cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile of the formula (I):
Figure imgf000015_0001
Formula (I) the process comprising a. condensing 4-halomethyl benzonitrile of the formula (II)
Figure imgf000016_0001
wherein X = Cl or Br or I
Formula (II) with alkali metal salts of 1,2,4-triazole of the formula (III b)
Figure imgf000016_0002
wherein M+ : Na+ / K+
Formula (III b) in an organic solvent at temperature of 40 to 100° C; b. charging 4-fluorobenzonitrile of the formula (V)
Figure imgf000016_0003
Formula (V) to the condensate in the presence of a base at temperature of - 5 to 5° C to obtain crude 4-[l-cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile of the formula
(I); c. isolating the crude compound of the formula (I) by extracting the reaction mixture with an organic solvent followed by distillation of the solvent under vacuum; and d1 purifying the compound of the formula (I) by column chromatography using a stationary phase and a mobile phase followed by recrystallization using an organic solvent.
12. The process as claimed in claim 11, wherein the alkali metal salts of 1,2,4-triazole of the formula (III b) used in step (a) are sodium or potassium salts.
13. The process as claimed in claim 11, wherein the organic solvent used in step (a) is selected from dipolar aprotic solvent such as dimethylsulphoxide, dimethylacetamide, 1,2- dimethoxy/diethoxyethane or dimethylforniamide; halo substituted or unsubstituted alkyl and aryl hydrocarbons such as hexane, toluene, xylene, methylene chloride, chloroform or dichloroethane; ketones such as acetone, methylisobutyl ketone or methylethylketone; nitriles such as acetonitrile; esters such as ethyl acetate; ethers such as diphenylether or diisopropyl ether; or alcohols such as ethanol, methanol, isopropanol or tert-butanol or mixtures thereof.
14. The process as claimed in claim 11, wherein the organic solvent used in step (a) is N3N- dimethylformamide or N,N-dimethylacetamide.
15. The process as claimed in claim 11, wherein the condensation of the compound of the formula (II) with 1,2,4- triazole of the formula (JR b) is carried out at temperature 40 to 7O0 C.
16. The process as claimed in claim 11, wherein the base used in step (b) is selected from organic base or inorganic base.
17. The process as claimed in claim 11, wherein the base used in step (b) is n-butyl lithium, sodium tertiary butoxide, potassium tertiary butoxide, potassium or sodium isopropoxide, potassium or sodium ethoxide, potassium or sodium methoxide, sodium hydride, lithium hydride, calcium hydride, triethylamine or diisopropyl ethyl amine.
18. The process as claimed in claim 11, wherein the compound of the formula (I) is isolated from the reaction mixture by extracting the reaction mixture with organic solvent selected from ethyl acetate, dichloromethane or chloroform.
19. The process as claimed in claim 11, wherein the stationary phase of the column chromatography used to purify the compound of the formula (T) is selected from silica gel or alumina.
20. The process as claimed in claim 11, wherein the mobile phase of the column chromatography used to purify the compound of the formula (T) is selected from aliphatic or aromatic hydrocarbons; alcohols; ketones or aliphatic solvents such as esters, mtriles; halogeneted solvent or mixtures thereof.
21. The process as claimed in claim 11, wherein the mobile phase of the column chromatography used to purify the compound of the formula (I) is mixture of ethylacetate- hexane or mixture of dichloromethane-acetonitrile.
22. The process as claimed in claim 11, wherein the organic solvent used in recrystallization of the compound of the formula (I) in step (d1) is selected from toluene, xylene, methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, iso-propyl acetate, petroleum ethers, hexane or water or mixtures thereof.
23. The process as claimed in claim 11, wherein the recrystallization of the compound of the formula (I) in step (d1) is carried out in a solvent selected from ethanol or mixture of ethanol-hexane.
24. 4-[l-cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile in high purity (> 99.6%) and high yield (about 40 to 60 %) prepared by the process as claimed in claiml.
25. 4-[l-cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile in high purity (> 99.6%) and high yield (about 40 to 60 %) prepared by the process as claimed in claim 12.
PCT/IN2005/000331 2005-10-05 2005-10-05 A one pot process for the preparation of 4-[1-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile WO2007039912A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IN2005/000331 WO2007039912A1 (en) 2005-10-05 2005-10-05 A one pot process for the preparation of 4-[1-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2005/000331 WO2007039912A1 (en) 2005-10-05 2005-10-05 A one pot process for the preparation of 4-[1-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile

Publications (1)

Publication Number Publication Date
WO2007039912A1 true WO2007039912A1 (en) 2007-04-12

Family

ID=36508202

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2005/000331 WO2007039912A1 (en) 2005-10-05 2005-10-05 A one pot process for the preparation of 4-[1-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile

Country Status (1)

Country Link
WO (1) WO2007039912A1 (en)

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
WO2010146391A1 (en) 2009-06-15 2010-12-23 Generics [Uk] Limited Regioselective synthesis of letrozole
WO2012025762A2 (en) 2010-08-27 2012-03-01 Generics [Uk] Limited Pure intermediate
US8198460B2 (en) 2007-11-28 2012-06-12 Fresenius Kabi Oncology Ltd. Process for preparation of letrozole and its intermediates
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
US4978672A (en) * 1986-03-07 1990-12-18 Ciba-Geigy Corporation Alpha-heterocyclc substituted tolunitriles
WO2004076409A2 (en) * 2003-02-06 2004-09-10 Sun Pharmaceutical Industries Limited Regiospecific process for the preparation of 4-[1- (4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4978672A (en) * 1986-03-07 1990-12-18 Ciba-Geigy Corporation Alpha-heterocyclc substituted tolunitriles
WO2004076409A2 (en) * 2003-02-06 2004-09-10 Sun Pharmaceutical Industries Limited Regiospecific process for the preparation of 4-[1- (4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CARROL TEMPLE: "1,2,4-Triazoles", 1981, JOHN WILEY, XP002384403 *

Cited By (9)

* 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
WO2010146391A1 (en) 2009-06-15 2010-12-23 Generics [Uk] Limited Regioselective synthesis of letrozole
WO2012025762A2 (en) 2010-08-27 2012-03-01 Generics [Uk] Limited Pure intermediate
WO2012025762A3 (en) * 2010-08-27 2012-05-03 Generics [Uk] Limited Pure intermediate for preparing letrozole
CN103298795A (en) * 2010-08-27 2013-09-11 基因里克斯(英国)有限公司 Pure intermediate for preparing letrozole
US9150524B2 (en) 2010-08-27 2015-10-06 Generics [Uk] Limited Pure intermediate
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

Similar Documents

Publication Publication Date Title
EP2024343B1 (en) Process for purification of anastrozole
WO2007144896A1 (en) A method of manufacture of letrozole
US7459565B2 (en) Regiospecific process for the preparation of 4-[1- (4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl] benzonitrile
EP0651748B1 (en) Process for preparing indole derivatives containing a 1,2,4-triazol-1-yl substituent
US7692025B2 (en) Process for the preparation of anticancer drugs
US7989636B2 (en) Process for the preparation of pure anastrozole
US10301289B2 (en) Method for the preparation of triazole compounds
WO2007039912A1 (en) A one pot process for the preparation of 4-[1-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile
US8003804B2 (en) Synthesis of 4-[1-(4-cyano phenyl)-(1,2,4-triazol-1-yl)methyl] benzonitrile and 4-[1-(1H-1,2,4-triazol-1-yl)methylene benzonitrile intermediate
US11518771B2 (en) Process for manufacturing alkyl 7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridine-carboxylate
KR100973616B1 (en) Method for preparing 1,2,4-triazolylmethyl-oxirane
US20080207915A1 (en) Process for the Preparation of 2,2'-[5-(1H-1,2,4-Triazole-1-Ylmethyl) -1,3-Phenylene] Di (2-Methylpropionitrile)
Kweon et al. Dehalogenation of 1‐methyl‐5‐halo‐4‐substituted‐pyridazin‐6‐ones
CN113527220A (en) Synthetic method of desulfurization prothioconazole isomer
US7601847B2 (en) Preparation and purification of 4-(indazol-3-yl)phenols
JP4754145B2 (en) Process for producing 2- (1,2,4-triazol-1-yl) -ethanols
CZ304209B6 (en) Process for preparing aryl triazolinones and novel intermediates for this process
US20070129414A1 (en) Process for preparing 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1h-imidazole-1-yl)methyl]- 4h-carbbazol-4-one or its salt
WO2009010991A2 (en) Purification process to prepare highly pure anastrozole
EP2456758B1 (en) A process for preparing trisubstituted phenyl derivatives comprising a (1h-1,2,4-triazol-1-yl)alkyl group
JP2003327586A (en) Method for producing triazolopyrimidine derivative
Campion et al. A new method of preparation of 1H‐1, 2‐benzodiazepines by the rearrangement of 2, 4, 6‐trichlorophenylhydrazones
KR20080112306A (en) 4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile and 4- [1- (1H-1,2,4-triazole Synthesis of -1-yl) methylene benzonitrile intermediate
PL204392B1 (en) Method of obtaining 2,2'-(5-(1H-1,2,4-triazol-1-)-ylmethyl)-1,3-phenylene)di(2-methylpropionitrile)

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 05823768

Country of ref document: EP

Kind code of ref document: A1

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载