WO2005047269A1 - A method for the separation of the letrozole precursor 4-‘1-(1,2,4-triazolyl) methyl!benzonitrile from its 1,3,4-triazolyl isomer - Google Patents
A method for the separation of the letrozole precursor 4-‘1-(1,2,4-triazolyl) methyl!benzonitrile from its 1,3,4-triazolyl isomer Download PDFInfo
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- WO2005047269A1 WO2005047269A1 PCT/IN2003/000357 IN0300357W WO2005047269A1 WO 2005047269 A1 WO2005047269 A1 WO 2005047269A1 IN 0300357 W IN0300357 W IN 0300357W WO 2005047269 A1 WO2005047269 A1 WO 2005047269A1
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- formula
- triazolyl
- methyl
- benzonitrile
- separation
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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
- This invention relates to an improved method for the preparation of letrozole precursor 5 from an isomeric mixture.
- Letrozole is an aromatase inhibitor drug used in the treatment of postmenopausal breast cancer.
- the intermediate 4-[l-(l,2,4- triazolyl)methyl]benzonirile of the formula (I) is commonly employed as a precursor in the manufacture of Letrozole
- the desired product of the formula (I) is separated from the impurities using column chromatography technique
- the column chromatography technique of the purification of the compound of the formula I suffers from the following set backs.
- Column chromatography technique is not adaptable for multi kilograms level manufacture as i.
- Special equipment [ columns] is to be designed in the plant. ⁇ .
- Solvents recovery is an important task, as inefficient solvent recovery effects the product costing considerably, vi. Large quantity of chromatography grade adsorbant is required which effects the economy of the process. vii. Specially trained personnel are required to perform column chromatography technique on a manufacturing scale in the plant.
- the main objective of the present invention is to provide an improved process for the separation of letrozole precursor 4-[l-l,2,4-triazolyl)methyl]benzonitrile of the formula (I) from the isomeric unwanted bye product 4-[l-(l,3,4- triazolyl)methyl]benzonitrile of formula (II) and other impurities avoiding the drawbacks of the hitherto known processes :
- Another objective of the present invention is to provide an improved process for the separation of letrozole precursor 4-[l-l,2,4-triazolyl)methyl]benzonitrile of the formula (I) from the isomeric unwanted by product 4-[l-(l,3,4-triazolyl)methyl]benzonitrile of formula (II) and other impurities avoiding column chromatography technique.
- Yet another objective of the present invention is to provide an improved process for the separation of letrozole precursor 4-[l-l,2,4-triazolyl)methyl]benzonitrile of the formula (I) from the isomeric unwanted by product 4-[l-(l,3,4-triazolyl)methyl]benzonitrile of formula (II) and other impurities resulting in efficient separation by a chemical method .
- Still another objective of the present invention is to provide an improved process for the separation of letrozole precursor 4-[l-l,2,4-triazolyl)methyl]benzonitrile of the formula (I) from the isomeric unwanted by product 4-[l-(l,3,4-triazolyl)methyl]benzonitrile of formula (II) and other impurities resulting in an end product having increased purity (99.7%) .
- Another objective of the present invention is to provide an improved process for the separation of letrozole precursor 4-[l-l,2,4-triazolyl)methyl]benzonitrile of the formula (I) from the isomeric unwanted by product 4-[l-(l,3,4-triazolyl)methyl]benzonitrile of formula (II) and other impurities using very mild conditions thereby making the process simple and safe .
- Still another objective of the present invention is to provide an improved process for the separation of letrozole precursor 4-[l-l,2,4-triazolyl)methyl]benzonitrile of the formula (I) from the isomeric unwanted by product 4-[l-(l,3,4-triazolyl)methyl]benzonitrile of formula (II) and other impurities avoiding the usage of special equipment whose procurement can be a deterrent for large scale manufacture.
- Yet another objective of the present invention is to provide an improved process for the separation of letrozole precursor 4-[l-l,2,4-triazolyl)methyl]benzonitrile of the formula (I) from the isomeric unwanted by product 4-[l-(l,3,4-triazolyl)methyl]benzonitrile of formula (II) and other impurities without using huge volumes of organic solvents thereby avoiding environmental hazards.
- Still another objective of the present invention is to provide an improved process for the separation of letrozole precursor 4-[l-l,2,4-triazolyl)methyl]benzonitrile of the formula (I) from the isomeric unwanted by product 4-[l-(l,3,4-triazolyl)methyl]benzonitrile of formula (II) and other impurities avoiding additional purification step and reducing operational time thereby making the process economical.
- Another objective of the present invention is to provide an improved process for the separation of letrozole precursor 4-[l-l,2,4-triazolyl)methyl]benzonitrile of the formula (I) from the isomeric unwanted by product 4-[l-(l,3,4-triazolyl)methyl]benzonitrile of formula (II) and other impurities which does not require employment of specially trained personnel.
- the present invention provides an improved method for the separation of compound of the formula (I) from the compound of formula of (II)
- step (a) of the process may be prepared as per the scheme shown in fig (I) described in US patent No 4,978,672 (1990) and EP 023940 (1981).
- step (a) the amount of dichloromethane or chloroform used with respect to the crude mixture weight may be in the range of 8 to 9 volumes preferably 8.5 volumes .
- step (c) the amount of isopropanolic HC1 (LPA-HC1) of 10 to 14 % concentration may be in the range of 0.2-0.3 volumes with respect to crude mixture weight preferably 0.26 volumes .
- the amount of isopropyl ether with respect to the crude mixture weight may be in the range of 8-9 volumes preferably 8.6 volumes .
- Example 1 The details of the inventions are given in the Example below which are provided for illustration only and therefore these examples should not be constructed to limit the scope of the invention.
- Example 1 The details of the inventions are given in the Example below which are provided for illustration only and therefore these examples should not be constructed to limit the scope of the invention.
- the mixture obtained as described in the step (a) is charged into the reactor.
- 30 L of dichloromethane is charged and stirred.
- 0.96 L of 10% IPA-HCl (w/v) is charged slowly during 20 minutes
- 30 L of isoprpyl ether is then charged.
- the mixture is stirred, centrifuged and washed with 3.5 L isopropyl ether.
- the reaction mixture is filtered and the compound of the formula (II) is unloaded and dried in oven [0.7 Kg; MR:147-151°C; Purity: 92%].
- the mother liquor containing the compound of the formula (I) are distilled completely under vacuum and the residue is partitioned in between 7.0 L of dilute sodium hydroxide solution and 3.5 L of dichloromethane.
- the mixture obtained as described in the step (a) is charged into the reactor. 30 L of chloroform is charged and stirred . 0.96 L of 14% IPA-HC1 (w/v) is charged slowly during 20 minutes 30 L of isoprpyl ether is then charged. The mixture is stined, centrifuged and washed with 3.5 L isopropyl ether. The reaction mixture is filtered and the compound of the formula (II) is unloaded and dried in oven [1.05 Kg; Purity: 60%]. The mother liquor containing the compound of the formula (I) is distilled completely under vacuum and the residue is partitioned in between 7.0L of dilute sodium hydroxide solution and 3.5 L of dichloromethane. The organic layer is separated and distilled off completely.
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A chemical method for the separation of letrozole precursor 4-[1-1,2,4-triazolyl)methyl]benzonitrile of formula (I) from the isomeric unwanted byproduct 4-[1-(1,3,4-triazolyl)methyl]benzonitrile of formula (II) of the reaction in which it is produced, which comprises (a) Preparing an isomeric mixtures of the compounds of formula (I) and (II) by conventional methods. (b) Dissolving the resultant crude isomeric mixture in dichloro methane (or) chloroform. (c) Adding 10-14% isopropylalcohol hydrochloride (IPACHI) to the resulting solution. (d) Adding isopropyl ether to precipitate undesired isomer is hydrochloride form. (e) Filtering off the undesired isomer hydrochloride. (f) Distilling off the filtrate completely. (g) Adding dilute sodium hydroxide solution and dichloromethane to the residue to liberate required isomer base of the formula (I). (h) Evaporating the separated dichloromethane layer and charging hexane or petroleum ether. (i) Centrifuging the resultant product of the formula (I) and washing with hexane or petroleum ether.
Description
A METHOD FOR THE SEPARATION OF THE LETROZOLE PRECURSER 4- v 1- (1 , 2 , -TRIAZOLYL) METHYL! BENZONITRILE FROM ITS 1, 3 , 4-TRIAZOLYL ISOMER
This invention relates to an improved method for the preparation of letrozole precursor 5 from an isomeric mixture. Letrozole is an aromatase inhibitor drug used in the treatment of postmenopausal breast cancer. The intermediate 4-[l-(l,2,4- triazolyl)methyl]benzonirile of the formula (I) is commonly employed as a precursor in the manufacture of Letrozole
0 The unwanted isomeric by product 4-[l-(l,3,4-triazolyl)methyl] benzonitrile of formula (II) is invariably produced during the synthesis of the intermediate 4-[l-(l,2,4- triazolyl)methyl]benzonirile of the formula (I) and cumbersome chromatrographic methods are used to separate the compound of the formula (I) from a mixture of the compounds of the formulae (I) and (II).
Processes for separating the compounds from mixtures are of great importance, both in the laboratory and on an industrial scale. The purity of chemical compounds is dictated to a large extent by the purification step in which a compound is separated from other products of the reaction in which it is produced. The separation of a compound from its isomers can be particularly difficult to achieve. Conventional methods for separating a compound from its isomers include crystallization, chromatography, fractional distillation and the like. But these techniques can be relatively expensive and time consuming and they do not always provide a sufficiently high degree of separation.
The Known method for the synthesis of the compound 4-[l-(l,2,4- triazolyl)methyl]benzonirile of the formula (I) , the key intermediate useful for the manufacture of letrozole is described in EP 0236940 (1987) US 4978672 (1990) .The process disclosed in the above patents is shown below in Fig (i) which produces isomeric
According to the process shown in fig (i) the reaction of refluxing alpha-bromo-4- tolunitrile of the formula (III) with 1,2,4-triazole of the formula (IV), potassium carbonate and potassium in the presence of acetone gives an isomeric mixture of 4-[l-(l,2,4- triazolyl)methyl] benzonitrile of the formula (I) and 4-[l-(l,3,4- triazolyl)methyl]benzonitrile of the formula (II) in 87:11 ratio along with 2% other impurities. This mixture of the products of the reaction is not disclosed in the above mentioned patents, but the indicated ratio is based on our experimental observation. The desired product of the formula (I) is separated from the impurities using column
chromatography technique The column chromatography technique of the purification of the compound of the formula I suffers from the following set backs. Column chromatography technique is not adaptable for multi kilograms level manufacture as i. Special equipment [ columns] is to be designed in the plant. ϋ. Even by employing large columns on commercial scale, a maximum of about 4 Kg of product only can be separated in one batch, requiring repeating a number of times to manufacture the product on a multi kilogram scale, iii. It is very time consuming as it requires slow elution for efficient separation . iv. It involves huge volumes of solvents which can harm the environment. v. Solvents recovery is an important task, as inefficient solvent recovery effects the product costing considerably, vi. Large quantity of chromatography grade adsorbant is required which effects the economy of the process. vii. Specially trained personnel are required to perform column chromatography technique on a manufacturing scale in the plant.
The above factors render the chromatography technique of purification of the compound of the formula I is unwieldy and unviable for the adaptation of the process on a commercial scale.
Summary of invention
Taking into consideration the above mentioned shortcomings of the chromatographic technique of purifying the compound of the formula I, our aim was directed towards developing an improved environmentally safe and industrially applicable technique, which is devoid of the insufficiencies of the known method and makes it possible the synthesis of pure desired compound namely the compound of the formula I in high yields.
Therefore the main objective of the present invention is to provide an improved process for the separation of letrozole precursor 4-[l-l,2,4-triazolyl)methyl]benzonitrile of the formula (I) from the isomeric unwanted bye product 4-[l-(l,3,4-
triazolyl)methyl]benzonitrile of formula (II) and other impurities avoiding the drawbacks of the hitherto known processes :
Another objective of the present invention is to provide an improved process for the separation of letrozole precursor 4-[l-l,2,4-triazolyl)methyl]benzonitrile of the formula (I) from the isomeric unwanted by product 4-[l-(l,3,4-triazolyl)methyl]benzonitrile of formula (II) and other impurities avoiding column chromatography technique.
Yet another objective of the present invention is to provide an improved process for the separation of letrozole precursor 4-[l-l,2,4-triazolyl)methyl]benzonitrile of the formula (I) from the isomeric unwanted by product 4-[l-(l,3,4-triazolyl)methyl]benzonitrile of formula (II) and other impurities resulting in efficient separation by a chemical method .
Still another objective of the present invention is to provide an improved process for the separation of letrozole precursor 4-[l-l,2,4-triazolyl)methyl]benzonitrile of the formula (I) from the isomeric unwanted by product 4-[l-(l,3,4-triazolyl)methyl]benzonitrile of formula (II) and other impurities resulting in an end product having increased purity (99.7%) .
Another objective of the present invention is to provide an improved process for the separation of letrozole precursor 4-[l-l,2,4-triazolyl)methyl]benzonitrile of the formula (I) from the isomeric unwanted by product 4-[l-(l,3,4-triazolyl)methyl]benzonitrile of formula (II) and other impurities using very mild conditions thereby making the process simple and safe .
Still another objective of the present invention is to provide an improved process for the separation of letrozole precursor 4-[l-l,2,4-triazolyl)methyl]benzonitrile of the formula (I) from the isomeric unwanted by product 4-[l-(l,3,4-triazolyl)methyl]benzonitrile of formula (II) and other impurities avoiding the usage of special equipment whose procurement can be a deterrent for large scale manufacture.
Yet another objective of the present invention is to provide an improved process for the separation of letrozole precursor 4-[l-l,2,4-triazolyl)methyl]benzonitrile of the formula (I) from the isomeric unwanted by product 4-[l-(l,3,4-triazolyl)methyl]benzonitrile of formula (II) and other impurities without using huge volumes of organic solvents thereby avoiding environmental hazards.
Still another objective of the present invention is to provide an improved process for the separation of letrozole precursor 4-[l-l,2,4-triazolyl)methyl]benzonitrile of the formula (I) from the isomeric unwanted by product 4-[l-(l,3,4-triazolyl)methyl]benzonitrile of formula (II) and other impurities avoiding additional purification step and reducing operational time thereby making the process economical.
Another objective of the present invention is to provide an improved process for the separation of letrozole precursor 4-[l-l,2,4-triazolyl)methyl]benzonitrile of the formula (I) from the isomeric unwanted by product 4-[l-(l,3,4-triazolyl)methyl]benzonitrile of formula (II) and other impurities which does not require employment of specially trained personnel.
Accordingly we found an excellent process in which the two isomers of formulae (I) and (II) can be separated efficiently by employing specific solvents and reagents in particular proportions. Further we emphasize that this purification process is possible only with below mentioned solvents in that particular proportions.
Accordingly, the present invention provides an improved method for the separation of compound of the formula (I) from the compound of formula of (II)
(a) Preparing an isomeric mixtures of the compounds of formula (I) and (II) by conventional methods . (b) Dissolving the resultant crude isomeric mixture in dichloro methane (or) chloroform.
(c) Adding isopropyl alcoholic hydrochloride (IPA.HC1) of 10 to 14% concentration to the resulting solution .
(d) Adding isopropyl ether to precipitate undesired isomer in hydrochloride form.
(e) Filtering off the undesired isomer of the formula (II) in hydrochloride form. (f) Distilling off the filtrate completely to get desired isomer of the formula(I) exclusively in hydrochloride form, (g) Partitioning the hydrochloride salt between dilute sodium hydroxide solution and dichloro methane to liberate required isomer base of the formula(I). (h) Distilling off the separated dichloromethane layer completely and to charge hexane or petroleum ether to the residue to get filterable compound .
(i) Centrifuging the resultant product of the formula I and washing with hexane or petroleum ether.
The isomeric mixture used in step (a) of the process may be prepared as per the scheme shown in fig (I) described in US patent No 4,978,672 (1990) and EP 023940 (1981).
In step (a) the amount of dichloromethane or chloroform used with respect to the crude mixture weight may be in the range of 8 to 9 volumes preferably 8.5 volumes .
In step (c) the amount of isopropanolic HC1 (LPA-HC1) of 10 to 14 % concentration may be in the range of 0.2-0.3 volumes with respect to crude mixture weight preferably 0.26 volumes .
In Step (d) the amount of isopropyl ether with respect to the crude mixture weight may be in the range of 8-9 volumes preferably 8.6 volumes .
The details of the inventions are given in the Example below which are provided for illustration only and therefore these examples should not be constructed to limit the scope of the invention.
Example 1
The separation of 4-(l-(l,3,4-triazolyl)methyl] benzonitrile of formula (I) from an isomeric mixture.
(a) Preparation of the mixture of Compounds of the formula I & H .
To a solution of 4.4 Kg of alpha-bromo-p-tolunitrile in 75 Lts of acetone are added sequentially 2.4 Kgs of 1,2,4-triazole, 3.12 Kgs of potassium carbonate and 0.2 Kgs of potassium iodide. The mixture stirred for 8 hours at 55°C, cooled to room temperature, filtered and evaporated. The residue is partitioned between methyl ene chloride and water. The organic phase is separated, washed with brine, dried over sodium sulphate and evaporated. The resulting crystalline crude is filtered after trituration with hexane (yield : 3.5 Kgs). Compounds of formulae (I), (II) and impurities are found in 87:11:2 ratio.
(b) Separation of the compound of the formula I from the mixture
The mixture obtained as described in the step (a) is charged into the reactor. 30 L of dichloromethane is charged and stirred. 0.96 L of 10% IPA-HCl (w/v) is charged slowly during 20 minutes 30 L of isoprpyl ether is then charged. The mixture is stirred, centrifuged and washed with 3.5 L isopropyl ether. The reaction mixture is filtered and the compound of the formula (II) is unloaded and dried in oven [0.7 Kg; MR:147-151°C; Purity: 92%]. The mother liquor containing the compound of the formula (I) are distilled completely under vacuum and the residue is partitioned in between 7.0 L of dilute sodium hydroxide solution and 3.5 L of dichloromethane. The organic layer is separated and distilled off completely. 10 L of hexane is charged to the residue and centrifuged. Dried under vacuum at 40-45°C [ 2.50 Kgs, 71% recovery] to obtain compound of the formula I having the Melting range : 79-80°C and Purity by HPLC -99.7%
Example 2
The separation of 4-(l-(l,3,4-triazoIyl)methyI] benzonitrile of formula (I) from an isomeric mixture
(a) Preparation of the mixture of Compounds of the formula I & H
To a solution of 4.4 Kg of alpha-bromo-p-tolunitrile in 75 Lts of acetone are added sequentially 2.4 Kgs of 1,2,4-triazole, 3.12 Kgs of potassium carbonate and 0.2 Kgs of potassium iodide. The mixture stirred for 8 hours at 55°C, cooled to room temperature, filtered and evaporated. The residue is partitioned between methylene chloride and water. The organic phase is separated, washed with brine, dried over sodium sulphate and evaporated. The resulting crystalline crude is filtered after trituration with hexane (yield : 3.5 Kgs) Compounds of formulae (I), (II) and impurities are found in 87: 11:2 ratio
(b) Separation of the compound of the formula I from the mixture
The mixture obtained as described in the step (a) is charged into the reactor. 30 L of chloroform is charged and stirred . 0.96 L of 14% IPA-HC1 (w/v) is charged slowly during 20 minutes 30 L of isoprpyl ether is then charged. The mixture is stined, centrifuged and washed with 3.5 L isopropyl ether. The reaction mixture is filtered and the compound of the formula (II) is unloaded and dried in oven [1.05 Kg; Purity: 60%]. The mother liquor containing the compound of the formula (I) is distilled completely under vacuum and the residue is partitioned in between 7.0L of dilute sodium hydroxide solution and 3.5 L of dichloromethane. The organic layer is separated and distilled off completely. 10 L of petroleum ether (60-80°c fraction) is charged to the residue and centrifuged. Dried under vacuum at 40-45°C [1.94 Kgs, 55.4% recovery] to obtain compound of the formula I having the Melting range: 79-80°C and Purity by HPLC -99.7%
Advantages of the present process
1) The process avoids column chromatography thereby making it simple and economical
2) The process is simple as it is based on chemical separation.
3) The isomer of the formula I is separated in more than 99.0% purity.
4) The isomer of the formula I is separated in very good yields.
5) The unwanted isomer of the formula II is also obtained which on further purification can be used for independent application in chemical synthesis.
6) The process can be used for commercial production.
7) The process is environmentally safe .
8) The process can be operated without employing any specially trained personnel.
Claims
WE CLAIM
1 An improved method for the separation of compound of the formula (I) from the compound of formula of (II)
Which comprises
(a) Preparing an isomeric mixtures of the compounds of formula (I) and (TJ) by conventional methods.
(b) Dissolving the resultant crude isomeric mixture in dichloro methane (or) chloroform.
(c) Adding 10 -14 % isopropylalcohol hydrochloride (IPA.HC1) to the resulting solution. (d) Adding isopropyl ether to precipitate undesired isomer in hydrochloride form.
(e) Filtering off the undesired isomer hydrochloride.
(f) Distilling off the filtrate completely.
(g) Adding dilute sodium hydroxide solution and dichloromethane to the residue to liberate required isomer base of the formula (I). (h) Evaporating the separated dichloromethane layer and charging hexane or petroleum ether, (i) Centrifuging the resultant product of the formula I and washing with hexane or petroleum ether.
2. An improved process as claimed in claim 1 wherein the isomeric mixture used in step (a) of the process may be prepared as per the scheme shown in fig (I) described in US patent No 4,978,672 (1990) and EP 023940 (1981).
3. An improved process as claimed in claims 1 & 2 wherein the amount of dichloromethane used in step (a) with respect to the crude mixture may be in the range of 8 - 9 volumes preferably 8.5 volumes .
4. An improved process as claimed in claims 1 to 3 wherein in step (c) the isopropanol alcohol HC1 (LPA-HG) of 10-14% concentration may be in the range of 0.2-0.3 volumes with respect to crude mixture by weight preferably 0.26 volumes.
5. An improved process as claimed in claims lto 4 wherein in Step (d) the amount of the isopropyl ether may be in the range of 8-9 preferably 8.6 volumes with respect to the crude mixture by weight.
6. An improved method for the separation of compound of the formula (I) from the compound of formula of (II) substantially as herein described with reference to the examples 1& 2.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2003/000357 WO2005047269A1 (en) | 2003-11-14 | 2003-11-14 | A method for the separation of the letrozole precursor 4-‘1-(1,2,4-triazolyl) methyl!benzonitrile from its 1,3,4-triazolyl isomer |
| AU2003282380A AU2003282380A1 (en) | 2003-11-14 | 2003-11-14 | A method for the separation of the letrozole precursor 4-1-(1,2,4-triazolyl) methyl benzonitrile from its 1,3,4-triazolyl isomer |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2003/000357 WO2005047269A1 (en) | 2003-11-14 | 2003-11-14 | A method for the separation of the letrozole precursor 4-‘1-(1,2,4-triazolyl) methyl!benzonitrile from its 1,3,4-triazolyl isomer |
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| Publication Number | Publication Date |
|---|---|
| WO2005047269A1 true WO2005047269A1 (en) | 2005-05-26 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2003/000357 WO2005047269A1 (en) | 2003-11-14 | 2003-11-14 | A method for the separation of the letrozole precursor 4-‘1-(1,2,4-triazolyl) methyl!benzonitrile from its 1,3,4-triazolyl isomer |
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| AU (1) | AU2003282380A1 (en) |
| WO (1) | WO2005047269A1 (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007054964A2 (en) * | 2005-10-20 | 2007-05-18 | Cadila Healthcare Limited | Process for the preparation of letrozole |
| WO2007100346A1 (en) * | 2005-07-06 | 2007-09-07 | Sicor, Inc. | Improved process for the preparation of letrozole |
| DE102006053594B4 (en) * | 2005-11-14 | 2008-08-07 | Chemagis Ltd. | Process for the purification of letrozole |
| US7538230B2 (en) | 2005-11-14 | 2009-05-26 | Chemagis Ltd. | Letrozole production process |
| 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 |
| CN103242251A (en) * | 2013-05-22 | 2013-08-14 | 哈药集团制药总厂 | Preparation method of letrozole |
| CN103601691A (en) * | 2013-10-17 | 2014-02-26 | 连云港杰瑞药业有限公司 | Preparation method of high purity 4-[1-(1,2,4-triazole)methyl]-cyanophenyl |
| WO2015029519A1 (en) * | 2013-09-02 | 2015-03-05 | 株式会社クレハ | Method for producing triazole compound |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0236940A2 (en) * | 1986-03-07 | 1987-09-16 | Ciba-Geigy Ag | Alpha-heterocycle substituted tolunitriles |
-
2003
- 2003-11-14 AU AU2003282380A patent/AU2003282380A1/en not_active Abandoned
- 2003-11-14 WO PCT/IN2003/000357 patent/WO2005047269A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0236940A2 (en) * | 1986-03-07 | 1987-09-16 | Ciba-Geigy Ag | Alpha-heterocycle substituted tolunitriles |
Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007100346A1 (en) * | 2005-07-06 | 2007-09-07 | Sicor, Inc. | Improved process for the preparation of letrozole |
| US7705159B2 (en) | 2005-07-06 | 2010-04-27 | Sicor, Inc. | Process for the preparation of letrozole |
| WO2007054964A3 (en) * | 2005-10-20 | 2007-07-12 | Cadila Healthcare Ltd | Process for the preparation of letrozole |
| WO2007054964A2 (en) * | 2005-10-20 | 2007-05-18 | Cadila Healthcare Limited | Process for the preparation of letrozole |
| DE102006053594B4 (en) * | 2005-11-14 | 2008-08-07 | Chemagis Ltd. | Process for the purification of letrozole |
| US7465749B2 (en) | 2005-11-14 | 2008-12-16 | Chemagis, Ltd. | Letrozole purification process |
| US7538230B2 (en) | 2005-11-14 | 2009-05-26 | Chemagis Ltd. | Letrozole production process |
| DE102006053594C5 (en) * | 2005-11-14 | 2012-12-06 | Chemagis Ltd. | Process for the purification 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 |
| JP2013536217A (en) * | 2010-08-27 | 2013-09-19 | ジェネリクス・［ユーケー］・リミテッド | Pure intermediate |
| US9150524B2 (en) | 2010-08-27 | 2015-10-06 | Generics [Uk] Limited | Pure intermediate |
| CN103242251A (en) * | 2013-05-22 | 2013-08-14 | 哈药集团制药总厂 | Preparation method of letrozole |
| CN103242251B (en) * | 2013-05-22 | 2015-07-15 | 哈药集团制药总厂 | Preparation method of letrozole |
| WO2015029519A1 (en) * | 2013-09-02 | 2015-03-05 | 株式会社クレハ | Method for producing triazole compound |
| CN103601691A (en) * | 2013-10-17 | 2014-02-26 | 连云港杰瑞药业有限公司 | Preparation method of high purity 4-[1-(1,2,4-triazole)methyl]-cyanophenyl |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2003282380A8 (en) | 2005-06-06 |
| AU2003282380A1 (en) | 2004-06-06 |
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