Preparation method of anastrozole

Abstract

The invention relates to a preparation method of anastrozole, which comprises the following steps: by taking methyl 3, 5-dibromobenzoate as a starting raw material, sequentially carrying out substitution, reduction, phosphorylation and N-alkylation to obtain anastrozole. The preparation method provided by the invention is a brand new technical route and is not reported in any literature and patent. According to the method, the yield of the product can be greatly improved, and the method is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic synthesis of drugs, in particular to a preparation method of anastrozole. BACKGROUND

[0002] Anastrozole is a third-generation aromatase inhibitor, developed by AstraZeneca, and first approved for marketing in 1995. By inhibiting aromatase (the key enzyme for converting androgens into estrogens), it significantly reduces estrogen levels in the body, thereby inhibiting the growth of estrogen-dependent breast cancer cells. It is mainly used for the treatment of hormone receptor-positive breast cancer, especially breast cancer in postmenopausal women. The trade name is Arimidex. It is sold in the form of tablets. The structural formula of anastrozole is as follows:

[0003]

[0004] Patent EP1705168A1 discloses a preparation method of anastrozole, and the synthetic route is as follows:

[0005]

[0006] Using mesitylene as the starting material, the product is obtained through five steps of bromination, cyanation, methylation, bromination and N-alkylation.

[0007] The synthetic method of this route has the following problems: (1) The selectivity of the first step of bromination is poor. Since the starting material has three reaction sites, 1,3,5-tribrominated product will be generated, the yield is low, and it is difficult to separate. (2) The third step of the reaction uses the highly toxic reagent iodomethane, which is harmful to personnel and is not suitable for industrial production. SUMMARY

[0008] In order to solve the problems of low synthesis yield, many side reactions and safety hazards in the preparation method of anastrozole in the prior art, the purpose of the present application is to provide a method for effectively preparing high-purity anastrozole with high yield.

[0009] The present application provides a method for preparing a compound shown in formula V, comprising the following steps:

[0010]

[0011] Step (3): under the protection of inert gas, the compound shown in formula III is reacted with o-phenylenephosphonic dichloride in a base and an organic solvent to generate a compound shown in formula IV;

[0012] Step (4): the compound of formula IV and an organic base are dissolved in an organic solvent A under inert gas protection, cooling, adding 1,2,4-triazole tetrahydrofuran solution, stirring to obtain the compound of formula V.

[0013] In some embodiments of the present application, the base in step (3) is selected from any one or a combination of triethylamine, diisopropylethylamine, pyridine, N,N-dimethylpyridine, N-methylpiperidine, 4-dimethylaminopyridine or N-methylmorpholine.

[0014] In some embodiments of the present application, the organic solvent in step (3) is selected from any one or a combination of tetrahydrofuran, dioxane, diethyl ether, dimethyl sulfoxide, N,N-dimethylformamide, acetone, acetonitrile, toluene, N-methylpyrrolidone.

[0015] In some embodiments of the present application, the organic base in step (4) is selected from any one or a combination of imidazole, triethylamine, pyridine, 2,6-lutidine, N,N-diisopropylethylamine, DMAP, etc., preferably a combination of 2,6-lutidine and N,N-diisopropylethylamine.

[0016] In some embodiments of the present application, the organic solvent A in step (4) is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene and acetonitrile, preferably tetrahydrofuran.

[0017] In some embodiments of the present application, the cooling temperature in step (4) is -25 to -15℃.

[0018] In some embodiments of the present application, the compound of formula III is prepared by the following method:

[0019]

[0020] Step (1): the compound of formula I reacts with 2-cyano-2-methylpropionic acid under the catalysis of a mixture of cuprous iodide and lithium iodide to form the compound of formula II;

[0021] Step (2): the compound of formula II reacts with a reducing agent in an alcohol solvent to form the compound of formula III.

[0022] In some embodiments of the present application, the alcohol solvent in step (2) is selected from methanol, ethanol, isopropanol, propanol or n-butanol.

[0023] In some embodiments of the present application, the reducing agent in step (2) is selected from any one or a combination of sodium borohydride, sodium cyanoborohydride, sodium boron hydride acetate or lithium aluminum hydride.

[0024] The beneficial technical effects of the present application are:

[0025] (1) The route of the present application is completely new, and no literature / patent reports have been found. The reaction has few impurities, high yield, and the intermediates and products are easy to purify. No column chromatography purification is needed, and only simple recrystallization operation can obtain a product with high purity. The anastrozole prepared meets the pharmacopoeia standard.

[0026] (2) The reaction route of the present application uses 3,5-dibromomethyl benzoate as the starting material, and the cyanation has good selectivity, which not only avoids the occurrence of side reactions, but also greatly improves the yield of the product.

[0027] (3) The reaction conditions of the present application are mild, do not involve harsh conditions, and the operations in the reaction are all conventional operations, which are suitable for large-scale production of anastrozole. DETAILED DESCRIPTION

[0028] Example 1

[0029] Step 1: Synthesis of compound II

[0030]

[0031] Take 3,5-dibromomethyl benzoate (10.00 g, 34.1 mmol), 2-cyano-2-methylpropionic acid (8.48 g, 75.0 mmol), cuprous iodide (0.65 g, 3.41 mmol) and lithium iodide (0.05 g, 0.38 mmol) in a reaction bottle, and then add 50 mL of N-methylpyrrolidone and 10 mL of toluene, heat to 110-120°C, and then add DBU (6.74 g, 44.3 mmol) dropwise. After the dropwise addition is completed, heat to 140-145°C, and TLC point plate reaction is complete. Stop the reaction, cool the reaction liquid to room temperature, filter, and concentrate the filtrate under reduced pressure. Add water and cyclohexane to make a slurry, and recrystallize the filter cake with methanol to obtain compound II (8.75 g, 32.4 mmol) with a yield of 95%.

[0032] Step 2: Synthesis of compound III

[0033]

[0034] Into a reaction flask, compound II (8.75 g, 32.4 mmol) was weighed, 80 mL of isopropyl alcohol was added, NaBH4(4.02 g, 64.8 mmol) and CuCl2(0.43 g, 3.24 mmol) were added in batches, the temperature was raised to 80 °C and the reaction was refluxed for 18 h, the reaction was stopped, the reaction liquid was reduced to room temperature, 35% NaOH solution (150 mL) was added, the solvent was removed under reduced pressure, dichloromethane (100 mL*3) was extracted, the organic phase was collected, and the solvent was removed under reduced pressure to obtain compound III (7.68 g, 31.8 mmol) with a yield of 98%.

[0035] Step 3: Synthesis of compound IV

[0036]

[0037] Under nitrogen protection, into a reaction flask, compound III (7.68 g, 31.8 mmol), 40 mL of tetrahydrofuran and DMAP (7.76 g, 63.6 mmol) were added, and the temperature was reduced to -10 to -5 °C while stirring. A solution of o-phenylenephosphonic dichloride (6.65 g, 34.98 mmol) in tetrahydrofuran (30 mL) was added dropwise with stirring. After the dropwise addition was completed, the temperature was slowly raised to room temperature and the reaction progress was detected by TLC. After the reaction was completed, the filter cake was washed with an appropriate amount of tetrahydrofuran,

[0038] The filtrate was evaporated under reduced pressure to remove the solvent, and the residue was added with 50 mL of water, ethyl acetate (50 mL*3) was extracted, the organic phase was collected, and the organic layer was successively washed with 100 mL of 5% sodium bicarbonate aqueous solution, 100 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain compound IV (12.36 g, 31.2 mmol) with a yield of 98%.

[0039] Step 4: Synthesis of compound V

[0040]

[0041] Into a reaction flask, was placed compound IV (12.36 g, 31.2 mmol), 50 mL of tetrahydrofuran, N,N-diisopropylethylamine (8.05 g, 62.4 mmol) and 2,6-dimethylpyridine (3.40 g, 31.2 mmol) under nitrogen protection. The solution was stirred and cooled to -20 to -15 °C. A solution of 1,2,4-triazole (2.37 g, 34.3 mmol) in 20 mL of tetrahydrofuran was added dropwise. After the addition was completed, the reaction was stirred at -20 to -15 °C for 3 to 4 hours. The reaction was slowly warmed to room temperature. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was removed by evaporation under reduced pressure. The residue was added to 100 mL of purified water and extracted with DCM (50 mL*3). The organic phase was collected and washed with 100 mL of 5% sodium bicarbonate aqueous solution, 100 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Ananazole (8.78 g, 30.0 mmol) was obtained by recrystallization from methanol with a yield of 95% and a HPLC purity of 99.88%.

[0042] Example 2

[0043] The other conditions and operations were the same as in Example 1, except that NaBH4 was replaced by an equimolar amount of LiAlH4 in step 2. Ananazole was finally obtained with a HPLC purity of 99.90% and a total yield of 89% of the four-step reaction based on 3,5-dibromobenzoic acid methyl ester.

[0044] Comparative Example 1: Repetition of patent EP1705168A1

[0045] Step 1: Synthesis of 3,5-dibromomethyltoluene

[0046] Into a reaction flask, was placed mesitylene (12 g, 100 mmol) and 300 g of cyclohexane. The solution was heated to about 70 °C. NBS (35 g, 210 mmol) and AIBN (0.46 g, 1.5 mmol) were added to the hot solution step by step. The mixture was heated to reflux for 30 minutes, and then cooled to room temperature. The mixture was filtered, and the filtrate was washed with water 3 times. The organic layer was concentrated to dryness under reduced pressure. Recrystallization was performed with EtOH / n-hexane to obtain 3,5-dibromomethyltoluene (5.6 g, 20 mmol) with a yield of 20%.

[0047] Step 2: Synthesis of 5-methyl-1,3-benzenediethanenitrile

[0048] To a reaction flask was added 3,5-dibromomethyltoluene (5.6 g, 20 mmol), NaCN (2.1 g, 44 mmol) and ethanol (50 mL) and heated to reflux for 2 hours. After the reaction was complete, the mixture was concentrated and extracted into ethyl acetate. After removing the solvent under reduced pressure, isopropanol recrystallization gave 5-methyl-1,3-benzenediethanenitrile (2.2 g, 13 mmol) in 65% yield.

[0049] Step 3: Synthesis of a,a,a',a'-tetramethyl-5-methyl-1,3-benzenediethanenitrile

[0050] NaH (1.80 g, 71 mmol) was added to a solution of 5-methyl-1,3-benzenediethanenitrile (2.2 g, 13 mmol) in DMF (30 mL). The mixture was stirred and cooled to about 10 °C. A solution of iodomethane (9.2 g, 65 mmol) in DMF (10 mL) was added slowly dropwise to the cooled mixture, controlling the temperature of the reaction mixture so that it did not exceed 35 °C. After the addition was complete, the mixture was stirred at room temperature for about 4 hours. The reaction was stopped, 20 mL of water was added and the mixture was extracted with ethyl acetate (20 mL*3), the organic phase was collected and the organic layer was concentrated to dryness to give a crude product, which was purified by crystallization in isopropanol to give purified a,a,a',a'-tetramethyl-5-methyl-1,3-benzenediethanenitrile (1.80 g, 8 mmol) in 60% yield.

[0051] Step 4: Synthesis of a,a,a',a'-tetramethyl-5-bromomethyl-1,3-benzenediethanenitrile

[0052] A,a,a',a'-tetramethyl-5-methyl-1,3-benzenediethanenitrile (1.80 g, 8 mmol) was weighed into a reaction flask, and a solution of NBS (1.60 g, 9.5 mmol) and AIBN (0.20 g, 1.2 mmol) in acetonitrile (10 mL) was added. The reaction was heated to reflux for 3 h. The reaction was stopped, 20 mL of water was added and the mixture was extracted with ethyl acetate (20 mL*3), the organic phase was collected and the organic layer was concentrated to dryness to give a crude product (2.4 g, 8 mmol), which was used directly without further purification.

[0053] Step 5: Synthesis of anastrozole

[0054] To a solution of α,α,α',α'-tetramethyl-5-bromomethyl-1,3-benzene- diacetonitrile (2.4 g, 8 mmol) in 20 mL of DMF was added sodium 1,2,4- triazole (0.73 g, 8 mmol). The mixture was stirred at room temperature for 1 h. The reaction was quenched with 20 mL of water and extracted with ethyl acetate (20 mL*3). The organic phase was collected and concentrated to dryness to give a crude product. The crude product was purified by column chromatography to give anastrozole (0.70 g, 2.4 mmol) in 30% yield based on mesitylene, and 2.3% overall yield based on five steps.

[0055] Obviously, the above examples are merely for the purpose of clearly illustrating the examples, but not the limitation of the embodiments. Based on the above description, other different forms of changes or variations can also be made by those skilled in the art. Here, all the embodiments are not required to be exhausted, and the obvious changes or variations derived therefrom are still within the protection scope of the present application.

Claims

1. A method for preparing the compound shown in formula V, characterized in that, The method comprises the following steps: Step (3): under the protection of inert gas, the compound shown as formula III is reacted with o-phenylenedichlorophosphonic acid in a base and an organic solvent to generate a compound shown as formula IV; Step (4): under the protection of inert gas, the compound shown as formula IV and an organic base are dissolved in an organic solvent A, cooling is performed, a 1,2,4-triazole tetrahydrofuran solution is added, and stirring is performed to obtain a compound shown as formula V.

2. The method for preparing the compound of formula V according to claim 1, characterized in that, The base in step (3) is selected from any one or a combination of multiple of triethylamine, diisopropylethylamine, pyridine, N,N-dimethylpyridine, N-methylpiperidine, 4-dimethylaminopyridine or N-methylmorpholine.

3. The method for preparing the compound of formula V according to claim 1, characterized in that, The organic solvent in step (3) is selected from any one or a combination of multiple of tetrahydrofuran, dioxane, diethyl ether, dimethyl sulfoxide, N,N-dimethylformamide, acetone, acetonitrile, toluene or N-methylpyrrolidone.

4. The method of claim 1, wherein the compound of formula V is prepared by the process comprising: ###0002### V The organic base in step (4) is selected from any one or a combination of multiple of imidazole, triethylamine, pyridine, 2,6-dimethylpyridine, N,N-diisopropylethylamine, DMAP and the like, and preferably a combination of 2,6-dimethylpyridine and N,N-diisopropylethylamine.

5. The method for preparing the compound of formula V according to claim 1, characterized in that, The organic solvent A in step (4) is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene and acetonitrile, and preferably tetrahydrofuran.

6. The method of claim 1, wherein the compound of formula V is prepared by the method comprising: ###0002### V The cooling temperature in step (4) is -25 to -15 ℃.

7. The method for preparing the compound of formula V according to claim 1, characterized in that, The compound shown as formula III is prepared by the following method: Step (1): the compound shown as formula I is reacted with 2-cyano-2-methylpropionic acid under the catalysis of a mixture of cuprous iodide and lithium iodide to generate a compound shown as formula II; Step (2): the compound shown as formula II is reacted with a reducing agent in an alcohol solvent to generate a compound shown as formula III.

8. The method of claim 7, wherein the compound of formula V is prepared by the process comprising: ###00006### V The alcohol solvent in step (2) is selected from methanol, ethanol, isopropanol, propanol or n-butanol.

9. The method for preparing the compound of formula V according to claim 7, characterized in that, The reducing agent in step (2) is selected from any one or a combination of multiple of sodium borohydride, sodium cyanoborohydride, sodium boron hydride acetate or lithium aluminum tetrahydride.

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