CN101074215A - Production of 1-[3,5-2(2,2-dimethyl) ethylcyano] benzyl triazole - Google Patents
Production of 1-[3,5-2(2,2-dimethyl) ethylcyano] benzyl triazole Download PDFInfo
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Abstract
Production of 1-(3,5-2(2,2-dimethyl) methyl cyanide) benzyl pyrrodiazole is carried out by taking 3,5-2(2,2-dimethyl) ethyl-methyl) toluene (II) as raw material, synthesizing to obtain anatritra intermediate 3,5-2(2,2-dimethyl) ethyl-methyl) toluene bromide (III) and reacting with 1,2,4-triazanezole to obtain final product. It's simple and convenient, has less impurities and better product quality.
Description
Technical field
The invention belongs to the pharmaceutical chemistry technical field.Be specifically related to 1-[3,5-two (2, the 2-dimethyl) second cyano group] phenmethyl triazole (Anastrozole, preparation method I).
Background technology
1-[3,5-two (2, the 2-dimethyl) second cyano group] (structural formula I Anastrozole) is selectivity nonsteroidal arimedex to phenmethyl triazole (Anastrozole), is mainly used in the treatment of treatment postmenopausal women metastatic breast cancer in late period at present clinically.
(EP:0296749, USP:4935437) synthetic route of being reported has two:
Synthetic route I is as follows:
This route is with 3, and 5-two brooethyl toluene are starting raw material, through cyaniding, methylate, bromination makes intermediate 3,5-two [(2, the 2-dimethyl) cyano methyl] toluene bromide (III), and then with 1,2, the reaction of 4-triazole sodium obtains final product Anastrozole (I), though this method step is few, but key intermediate 3, the preparation aftertreatment complexity of 5-two [(2, the 2-dimethyl) cyano methyl] toluene, yield is low, and last end product demand pole chromatographic separation, be not suitable for industrial production.
Synthetic route II is as follows:
This route is with 3, and 5-mesitylenic acid methyl esters is a starting raw material, through bromination, cyaniding, methylate, and reduction, bromination again, N-alkylation 6 step reaction makes Anastrozole.This route final step is with 1,2, and the 4-triazole has replaced 1,2 among the route I, 4-triazole sodium, and weak point is that synthetic route is long, complex process, starting raw material 3,5-mesitylenic acid methyl esters and borane reducing agent sodium hydride cost an arm and a leg, and reaction yield is lower.(＜50％)。
The Ge Zemei of College of Pharmacy, Beijing Univ etc. (Chinese pharmaceutical chemistry magazine, 2003,13 (3), 146-147) to have designed new synthetic route as follows for some advantages among conjunctive path I and the route II:
Phase transfer catalysis process is adopted in this route final step, and the reaction times, the 18h by document shortened to 7h, and the purifying of end product adopts recrystallization method, helps suitability for industrialized production.Its weak point is the Anastrozole finished product purity that adopts this route to make not high (relative substance＞1%).
Summary of the invention:
Technical problem to be solved by this invention is to overcome above-mentioned weak point a kind of 1-[3 is provided, 5-two (2, the 2-dimethyl) second cyano group] phenmethyl triazole (Anastrozole, improvement preparation method I).The inventive method uses 3,5-two [(2, the 2-dimethyl) cyano methyl] toluene (II) obtains the intermediate 3 of Anastrozole for the raw material bromination, 5-two [(2, the 2-dimethyl) cyano methyl] toluene bromide (III) is then with 1,2, the condensation of 4-triazole obtains 1-[3,5-two (2, the 2-dimethyl) second cyano group] phenmethyl triazole (I).
The 1-[3 that the present invention relates to, 5-two (2, the 2-dimethyl) second cyano group] the phenmethyl triazole (Anastrozole, synthetic route I) is as follows:
In the method for the invention from 3,5-two [(2, the 2-dimethyl) cyano methyl] toluene bromide (III) and 1,2, the reaction of 4-triazole obtains 1-[3, and 5-two (2, the 2-dimethyl) second cyano group] employed reaction reagent is methylene dichloride or ethyl acetate in the step of phenmethyl triazole (I), phase-transfer catalyst is Tetrabutyl amonium bromide, tetrabutylammonium iodide or 4-propyl bromide, and temperature of reaction is 20～40 ℃, and the reaction times is 6～10 hours.In 0296749 synthetic route of being reported of comparing, N is adopted in this step reaction, and dinethylformamide is a reaction reagent, needs reaction 18h, long reaction time, and yield low (＜50%) is not suitable for suitability for industrialized production.This step reaction is a reaction reagent with dimethylbenzene in the designed synthetic route such as Ge Zemei, needs high temperature reflux to react 7h.Its shortcoming is that temperature of reaction is higher, can produce more side reaction, thereby influences final product quality.
1-[3 of the present invention, 5-two (2, the 2-dimethyl) second cyano group] (its another feature is a post-treating method to the phenmethyl triazole for Anastrozole, preparation method I).This method is: earlier reaction solution is concentrated into dried oily matter, adds hydrochloric acid oily matter is dissolved, and the elimination insolubles, filtrate is transferred pH=8～9 with sodium hydroxide, separates out solid, suction filtration, oven dry promptly gets Anastrozole finished product (I).The three batches of finished product differential thermal analysis of Anastrozole, powder x-ray diffraction and the particle diameter collection of illustrative plates that make with this method all are consistent, and accompanying drawing is seen Fig. 1-3.Relatively should go on foot reacting final product demand pole chromatographic separation in the 0296749 described synthetic route, be not suitable for industrial production.The end product purifying adopts ethyl acetate-sherwood oil recrystallization method in the described synthetic route such as Ge Zemei, but product purity lower (＞1%) needs repeatedly recrystallization, and reaction efficiency is not high.
The inventor finds easily to generate a kind of impurity in research and design present method in reaction process, and its possible structure is α, α, α ', α '-tetramethyl--5-(1 hydrogen-1,3,4-triazole-1-methyl)-1,3-diethyl itrile group benzene
The infared spectrum of this impurity is similar to Anastrozole, and mass spectrum is identical, is the isomer of Anastrozole, on carbon that the NMR collection of illustrative plates is close with the triazole ring and the triazole ring chemical shift of carbon atom different, collection of illustrative plates is seen Fig. 4.The approach that this impurity produces may be: 1. raw material 1,2, the 4-triazole may have 1,3, the 4-triazole participates in reaction and produces.2. the isomerization of reaction process molecule produces.We must control the purity that adapts to starting raw material, 1,2,4-triazole content answers＞98%, thereby the control reaction conditions, should control low-temp reaction as temperature as far as possible, can effectively prevent the generation of this isomer, through overtesting, it is＜0.1% that method of the present invention can effectively be controlled the content of this isomer in the Anastrozole finished product, and its HPLC collection of illustrative plates can be proved conclusively (Fig. 5).
The invention has the advantages that in a word, all raw materials that use more are easy to get, more economical, the reaction conditions gentleness, post-treating method is simple, favourable removal impurity, do not need to prepare and adopt column chromatography to separate or the complicated post-treating method of recrystallization repeatedly by pyroreaction, whole synthetic route only needs the operation of 2 steps, and is simpler and more direct, more practical, the present invention is more suitable for suitability for industrialized production.
The invention has the advantages that and use the raw material 3 that is easy to get on the market, 5-two [(2, the 2-dimethyl) cyano methyl] toluene, replace tetracol phenixin as reaction solvent with the lower chloroform of toxicity, syntheticly obtain 3,5-two [(2, the 2-dimethyl) cyano methyl] toluene bromide (III), with 1,2, the reaction of 4-triazole obtains Anastrozole (I) then.Reaction only needed for two steps, and reaction conditions is: with methylene dichloride or ethyl acetate is reaction reagent, because 1,2, the 4-triazole is insoluble to methylene dichloride or ethyl acetate, use Tetrabutyl amonium bromide, tetrabutylammonium iodide or 4-propyl bromide to accelerate reaction process, improve yield as phase-transfer catalyst.Temperature of reaction is 20～40 ℃ simultaneously, and the reaction times is 6～10 hours, and reaction conditions is relatively gentleer, not only is fit to suitability for industrialized production, has also avoided the generation of more side reaction, can better remove impurity, improves the quality of products.
Description of drawings:
Fig. 1 (A) Anastrozole differential thermal analysis collection of illustrative plates (lot identification mark: 051001).
Fig. 1 (B) Anastrozole differential thermal analysis collection of illustrative plates (lot identification mark: 051002).
Fig. 1 (C) Anastrozole differential thermal analysis collection of illustrative plates (lot identification mark: 051003).
Fig. 2 (A) Anastrozole X-ray diffracting spectrum (lot identification mark: 051001).
Fig. 2 (B) Anastrozole X-ray diffracting spectrum (lot identification mark: 051002).
Fig. 2 (C) Anastrozole X-ray diffracting spectrum (lot identification mark: 051003).
Fig. 3 (A) Anastrozole particle diameter collection of illustrative plates (lot identification mark: 051001).
Fig. 3 (B) Anastrozole particle diameter collection of illustrative plates (lot identification mark: 051002).
Fig. 3 (C) Anastrozole particle diameter collection of illustrative plates (lot identification mark: 051003).
Fig. 4 Anastrozole impurity A high performance liquid phase collection of illustrative plates.
Fig. 5 (A) Anastrozole high performance liquid phase collection of illustrative plates (lot identification mark: TH-4).
Fig. 5 (B) Anastrozole high performance liquid phase collection of illustrative plates (lot identification mark: 060106).
Fig. 5 (C) Anastrozole high performance liquid phase collection of illustrative plates (lot identification mark: 060101).
Fig. 5 (D) Anastrozole high performance liquid phase collection of illustrative plates (lot identification mark: 060203).
Embodiment:
Embodiment 1:
With 30g3,5-two [(2, the 2-dimethyl) cyano methyl] toluene, N-bromo-succinimide 30.7g, benzoyl peroxide 1.6g and tetracol phenixin 300ml add in the reaction flask, reflux and stir 2h, cooling, filtration, filter residue is washed 2 times with tetracol phenixin, boils off solvent, gets faint yellow solid 30.5g, be 3,5-two [(2, the 2-dimethyl) cyano methyl] toluene bromide (III), the not purified the next step that is directly used in.
With 1,2,4-triazole 7.2g, Anhydrous potassium carbonate 14.6g, potassium hydroxide 5.9g, Tetrabutyl amonium bromide 1.8g, methylene dichloride 200ml and intermediate III 30.5g add in the reaction flask successively, 20 ℃ of insulated and stirred, TLC detects (GF254 plate, petroleum ether-ethyl acetate, V: V=3: 1), about 10h reacts completely, reaction solution is concentrated into dried oily matter, add 1 equivalent hydrochloric acid 200ml oily matter is dissolved, the elimination insolubles adds sodium hydroxide 7.2g and transfers PH=8～9 in the filtrate, separate out solid, suction filtration, oven dry promptly gets Anastrozole finished product 22g.
(yield: 75.1%
mp：82～83℃
Related substance: total impurities: 0.11%, impurity A: 0.045%
Proterties: white crystalline powder
Lot number: TH-4)
Embodiment 2:
With 30g3,5-two [(2, the 2-dimethyl) cyano methyl] toluene, N-bromo-succinimide 30.7g, benzoyl peroxide 1.6g and chloroform 300ml add in the reaction flask, reflux and stir 2h, cooling, filtration, filter residue is washed 2 times with chloroform, boils off solvent, gets faint yellow solid 32g, be 3,5-two [(2, the 2-dimethyl) cyano methyl] toluene bromide (III), the not purified the next step that is directly used in.
With 1,2,4-triazole 7.6g, Anhydrous potassium carbonate 15.3g, potassium hydroxide 6.2g, tetrabutylammonium iodide 1.9g, ethyl ester ethyl ester 200ml and intermediate III 32g add in the reaction flask successively, 40 ℃ of insulated and stirred, TLC detects (GF254 plate, petroleum ether-ethyl acetate, V: V=3: 1), about 6h reacts completely, reaction solution is concentrated into dried oily matter, add 1 equivalent hydrochloric acid 200ml oily matter is dissolved, the elimination insolubles adds sodium hydroxide 7.5g and transfers PH=8～9 in the filtrate, separate out solid, suction filtration, oven dry promptly gets Anastrozole finished product 22.3g.
(yield: 72.6%
mp：81.5～82℃
Related substance: total impurities: 0.2%, impurity A: 0.012%
Proterties: white crystalline powder
Lot number: 060106)
Embodiment 3:
With 30g3,5-two [(2, the 2-dimethyl) cyano methyl] toluene, N-bromo-succinimide 30.7g, benzoyl peroxide 1.6g and chloroform 300ml add in the reaction flask, reflux and stir 2h, cooling, filtration, filter residue is washed 2 times with chloroform, boils off solvent, gets faint yellow solid 31g, be 3,5-two [(2, the 2-dimethyl) cyano methyl] toluene bromide (III), the not purified the next step that is directly used in.
With 1,2,4-triazole 7.4g, Anhydrous potassium carbonate 15.1g, potassium hydroxide 6.1g, Tetrabutyl amonium bromide 1.7g, methylene dichloride 200ml and intermediate III 31g add in the reaction flask successively, 30 ℃ of insulated and stirred, TLC detects (GF254 plate, petroleum ether-ethyl acetate, V: V=3: 1), about 7.5h reacts completely, reaction solution is concentrated into dried oily matter, add 1 equivalent hydrochloric acid 200ml oily matter is dissolved, the elimination insolubles adds sodium hydroxide 6.9g and transfers PH=8～9 in the filtrate, separate out solid, suction filtration, oven dry promptly gets Anastrozole finished product 22.1g.
(yield: 74.2%
mp：82.5～83℃
Related substance: total impurities: 0.17%, impurity A: 0.0295%
Proterties: white crystalline powder
Lot number: 060101)
Embodiment 4:
With 30g3,5-two [(2, the 2-dimethyl) cyano methyl] toluene, N-bromo-succinimide 30.7g, benzoyl peroxide 1.6g and chloroform 300ml add in the reaction flask, reflux and stir 2h, cooling, filtration, filter residue is washed 2 times with chloroform, boils off solvent, gets faint yellow solid 33.2g, be 3,5-two [(2, the 2-dimethyl) cyano methyl] toluene bromide (III), the not purified the next step that is directly used in.
With 1,2,4-triazole 7.8g, Anhydrous potassium carbonate 15.9g, potassium hydroxide 6.4g, Tetrabutyl amonium bromide 1.9g, ethyl ester ethyl ester 200ml and intermediate III 33.2g add in the reaction flask successively, 25 ℃ of insulated and stirred, TLC detects (GF254 plate, petroleum ether-ethyl acetate, V: V=3: 1), about 8.5h reacts completely, reaction solution is concentrated into dried oily matter, add 1 equivalent hydrochloric acid 200ml oily matter is dissolved, the elimination insolubles adds sodium hydroxide 7.1g and transfers PH=8～9 in the filtrate, separate out solid, suction filtration, oven dry promptly gets Anastrozole finished product 24.2g.
(yield: 75.2%
mp：82.5～83.5℃
Related substance: total impurities: 0.31%, impurity A: 0.035%
Proterties: white crystalline powder
Lot number: 060203)
Claims (4)
1, a kind of 1-[3,5-two (2, the 2-dimethyl) second cyano group] preparation method of phenmethyl triazole, it is characterized in that this method is with 3,5-two [(2, the 2-dimethyl) cyano methyl] toluene II is the synthetic intermediate 3 that obtains of raw material, 5-two [(2, the 2-dimethyl) cyano methyl] toluene bromide III, then with 1,2, the reaction of 4-triazole obtains 1-[3,5-two (2, the 2-dimethyl) second cyano group] phenmethyl triazole I, reaction formula is as follows:
2,1-[3 according to claim 1,5-two (2, the 2-dimethyl) second cyano group] preparation method of phenmethyl triazole, it is characterized in that wherein used solvent is a chloroform.
3,1-[3 according to claim 1,5-two (2, the 2-dimethyl) second cyano group] preparation method of phenmethyl triazole, it is characterized in that from 3 5-two [(2, the 2-dimethyl) cyano methyl] toluene bromide III and 1,2, the reaction of 4-triazole obtains 1-[3, and 5-two (2, the 2-dimethyl) second cyano group] in the preparation of phenmethyl triazole I, employed reaction reagent is methylene dichloride or ethyl acetate; Phase-transfer catalyst is Tetrabutyl amonium bromide, tetrabutylammonium iodide or 4-propyl bromide, and temperature of reaction is 20～40 ℃; Reaction times is 6～10 hours.
4,1-[3 according to claim 1 and 2,5-two (2, the 2-dimethyl) second cyano group] preparation method of phenmethyl triazole I, it is characterized in that its intermediate III and 1,2,4, the reacted treatment process of-ribavirin is: earlier reaction solution is concentrated into dried oily matter, adding hydrochloric acid dissolves oily matter, the elimination insolubles, it is 8～9 that filtrate is transferred pH with sodium hydroxide, separates out solid, suction filtration, oven dry promptly gets Anastrozole finished product I.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102108066A (en) * | 2011-02-17 | 2011-06-29 | 漯河南街村全威制药股份有限公司 | Method for synthesizing anastrozole |
| CN102050775B (en) * | 2009-11-11 | 2012-06-13 | 常州市第四制药厂有限公司 | Anastrozole impurity alpha, alpha, alpha', alpha'-tetramethyl-5-(succinimide-1-methyl)-1,3-phenyl diacetonitrile and preparation method thereof |
| CN102050796B (en) * | 2009-11-11 | 2012-09-26 | 常州市第四制药厂有限公司 | Method for preparing alpha,alpha,alpha',alpha'-tetramethyl-5-(1H-1,3,4-triazole-1-ylmethyl)-1,3-phenylenediacetonitrile |
| CN103554041A (en) * | 2013-11-12 | 2014-02-05 | 江苏正大清江制药有限公司 | Method for preparing anastrozole |
| CN108997236A (en) * | 2018-07-31 | 2018-12-14 | 重庆华邦制药有限公司 | A kind of preparation method of Anastrozole impurity |
-
2006
- 2006-05-17 CN CNB2006100266157A patent/CN100564365C/en active Active
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102050775B (en) * | 2009-11-11 | 2012-06-13 | 常州市第四制药厂有限公司 | Anastrozole impurity alpha, alpha, alpha', alpha'-tetramethyl-5-(succinimide-1-methyl)-1,3-phenyl diacetonitrile and preparation method thereof |
| CN102050796B (en) * | 2009-11-11 | 2012-09-26 | 常州市第四制药厂有限公司 | Method for preparing alpha,alpha,alpha',alpha'-tetramethyl-5-(1H-1,3,4-triazole-1-ylmethyl)-1,3-phenylenediacetonitrile |
| CN102108066A (en) * | 2011-02-17 | 2011-06-29 | 漯河南街村全威制药股份有限公司 | Method for synthesizing anastrozole |
| CN103554041A (en) * | 2013-11-12 | 2014-02-05 | 江苏正大清江制药有限公司 | Method for preparing anastrozole |
| CN103554041B (en) * | 2013-11-12 | 2016-02-03 | 江苏正大清江制药有限公司 | A kind of synthesis technique preparing Anastrozole |
| CN108997236A (en) * | 2018-07-31 | 2018-12-14 | 重庆华邦制药有限公司 | A kind of preparation method of Anastrozole impurity |
| CN108997236B (en) * | 2018-07-31 | 2021-09-14 | 重庆华邦制药有限公司 | Preparation method of anastrozole impurity |
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Assignee: Pharmaceutical Co., Ltd., Changzhou Pharmaceutical Factory No.4 Assignor: Changzhou City No.4 Pharmaceutical Factory Co., Ltd. Contract record no.: 2011320001105 Denomination of invention: New polypeptide human superoxide dismutase-1-13 and its encoding polynucleotides Granted publication date: 20091202 License type: Exclusive License Open date: 20071121 Record date: 20110825 |