Synthetic method of anastrozole intermediate

Abstract

The invention relates to the technical field of medicine synthesis, in particular to a synthesis method of an anastrozole intermediate. The synthesis method comprises the following steps: S1, adding a first solvent into 3, 5-bis [(2, 2-dimethyl) ethyl cyano] toluene serving as a raw material, mixing, then adding N-bromo-butanediimine, and carrying out substitution reaction to obtain a reaction mixed solution; s2, adding diethyl phosphite and organic alkali into the reaction mixed solution at room temperature, and reacting to obtain a finished product reactant system; s3, carrying out post-treatment on the finished product reactant system to obtain a crude anastrozole intermediate; s4, mixing the anastrozole intermediate crude product with a refining solvent, and refining to obtain a refining system; sequentially carrying out crystallization and suction filtration on the refining system to obtain a filter cake; and sequentially washing and drying the filter cake to obtain a finished product anastrozole intermediate. The method has the advantages of easily available raw materials, low cost, efficient reaction, high conversion rate, high product purity and the like.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical synthesis, in particular to a method for synthesizing anastrozole intermediate. Background Art

[0002] Anastrozole, chemically known as α,α,α',α'-tetramethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylacetonitrile, is a third-generation, highly effective, and selective non-steroidal aromatase inhibitor developed by AstraZeneca (UK). It was launched in 1995 under the trade name Arimidex. It significantly reduces serum estradiol levels and is clinically used to treat advanced breast cancer in postmenopausal women who are refractory to tamoxifen and other anti-estrogen therapies. Side effects are inevitable in organic processes, and for pharmaceuticals, these side effects can generate impurities. To ensure drug safety, the levels of impurities are clearly defined in various pharmacopoeias. Therefore, impurity research is crucial for pharmaceuticals.

[0003]

[0004] The preparation route of anastrozole is to use 3,5-bis[(2,2-dimethyl)acetylcyano]toluene and NBS as starting materials to react to obtain anastrozole intermediate, which is then reacted with sodium triazole to prepare anastrozole. The reaction formula of this route is as follows:

[0005]

[0006] Experimental studies have shown that when preparing a key anastrozole intermediate, the reaction between 3,5-bis(2,2-dimethyl)acetylcyano)toluene and NBS produces not only the intermediate but also a dibrominated product, with the ratio reaching as high as 4:3. Furthermore, due to the similar structural polarity of the two compounds, conventional methods are difficult to remove. This results in low raw material utilization and high production costs. Therefore, developing an efficient synthesis method for anastrozole intermediates is of great significance. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to overcome the shortcomings of the existing technology and provide a method for synthesizing an anastrozole intermediate. The present invention uses 3,5-bis[(2,2-dimethyl)acetylcyano]toluene as a raw material, and undergoes a substitution reaction with N-bromobutyleneimide (NBS) in a suitable solvent to produce a mixture containing an anastrozole intermediate and a dibromide. Subsequently, the dibromide is converted into an anastrozole intermediate by adding diethyl phosphite and an organic base. This synthesis method improves the utilization rate of the raw material 3,5-bis[(2,2-dimethyl)acetylcyano]toluene and the yield of the anastrozole intermediate, thereby reducing production costs.

[0008] The technical solution adopted by the present invention to solve its technical problem is:

[0009] A method for synthesizing anastrozole intermediate specifically comprises the following steps:

[0010] Step S1, using 3,5-bis[(2,2-dimethyl)acetylcyano]toluene as a raw material, adding a first solvent and mixing, and then adding N-bromobutylene imine (NBS) to cause a substitution reaction to obtain a reaction mixture;

[0011] Step S2, adding diethyl phosphite and an organic base to the reaction mixture obtained in step S1 at room temperature, and reacting to obtain a finished reactant system;

[0012] The finished product reaction system obtained in step S3 and step S2 is post-treated to obtain a crude anastrozole intermediate;

[0013] Step S4: mixing the crude anastrozole intermediate obtained in step S3 with a refining solvent and refining the mixture to obtain a refined system; sequentially crystallizing and filtering the refined system to obtain a filter cake; and sequentially washing and drying the filter cake to obtain a finished anastrozole intermediate.

[0014] The above synthesis reaction is:

[0015]

[0016] Furthermore, in step S1, the first solvent is selected from one or more of dichloromethane (DCM), dichloroethane (DCE), and tetrahydrofuran (THF). Selecting dichloromethane, dichloroethane, or tetrahydrofuran as a solvent can effectively dissolve the raw materials and stabilize the reaction system to avoid side reactions; moderate polarity is conducive to the substitution reaction, and also facilitates subsequent liquid separation operations, thereby improving reaction efficiency.

[0017] Furthermore, in step S1, the mass ratio of 3,5-di[(2,2-dimethyl)acetylcyano]toluene to the first solvent is 1:(5-10) to ensure sufficient dissolution and avoid side reactions caused by excessive concentration;

[0018] The molar ratio of 3,5-bis[(2,2-dimethyl)acetylcyano]toluene to N-bromobutylene imine is 1:(1.2-2.0), which ensures complete bromination while avoiding excessive reagent waste or by-product generation.

[0019] Furthermore, in step S1, the reaction temperature of the substitution reaction is 10 to 30° C., and the reaction time is 16 to 48 hours. This reaction temperature is mild and reduces energy consumption, avoids side reactions caused by high temperature (such as excessive bromination or solvent volatilization), and ensures the reaction rate. This reaction time allows for sufficient reaction, ensures the complete substitution reaction, improves the conversion rate, and reduces the residual unreacted raw materials.

[0020] Furthermore, in step S2, the organic base is selected from one or more of 4-dimethylaminopyridine (DMAP), N,N-diisopropylethylamine (DIPEA), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The use of the above organic bases can promote the nucleophilic substitution reaction of diethyl phosphite, improve the reaction efficiency, and avoid side reactions caused by strong bases.

[0021] Furthermore, in step S2, the reaction time is 3 to 5 hours, which can ensure the complete reaction of step S2 while avoiding product decomposition caused by prolonged reaction.

[0022] Furthermore, in step S3, the specific post-treatment operation is as follows: adding water to the finished reactant system obtained in step S2, separating the liquids, extracting the aqueous phase with DCM three times, combining the organic phases, washing the organic phases with saturated NaHCO3 and saturated NaCl twice each, drying over anhydrous Na2SO4, and concentrating to obtain a crude anastrozole intermediate.

[0023] During post-processing:

[0024] Liquid separation and extraction effectively remove water-soluble impurities (such as unreacted N-bromobutyleneimide or inorganic salts);

[0025] Saturated NaHCO3 washing to neutralize residual acidic substances and prevent equipment corrosion;

[0026] Saturated NaCl washing reduces emulsification and promotes stratification;

[0027] Drying with anhydrous Na2SO4 completely removes moisture to avoid product decomposition during subsequent concentration or refining.

[0028] Furthermore, in step S4, the refining solvent is selected from one or more of ethyl acetate, methyl tert-ether, and petroleum ether. A mixed solvent of ethyl acetate, methyl tert-ether, or petroleum ether can achieve solubility separation of impurities in the crude product by polarity differences, thereby improving refining efficiency. At the same time, the low-boiling point solvent is easy to recycle and reduce production costs.

[0029] Furthermore, in step S4, the refining operation is carried out under reflux conditions, the refining temperature is 85-95°C, and the refining time is 1 hour. Reflux refining (85-95°C) can promote complete dissolution of the crude product, and the 1 hour time balances energy consumption and efficiency, and the product has a more uniform crystal form after crystallization.

[0030] Furthermore, in step S4, the crystallization temperature is 0-5° C. This temperature can promote the formation of high-purity crystals, reduce impurity inclusion, and improve the purity of the filter cake. At the same time, the low temperature condition inhibits product degradation and improves the final yield.

[0031] The reaction mechanism of the present invention is as follows:

[0032] The reaction mechanism of step S1 is as follows: NBS first undergoes homolysis to produce bromine radicals and succinimide radicals (this process is chain initiation), followed by the bromine radical capturing hydrogen from the benzyl group to generate hydrogen bromide and a more stable benzyl radical. The hydrogen bromide reacts with NBS to produce succinimide and liquid bromine. The benzyl radical attacks the liquid bromine to produce a monosubstituted product and a bromine radical. The bromine radical then continues to capture hydrogen from the benzyl group of the monosubstituted product to produce hydrobromic acid and a bromine-substituted benzyl radical. The bromine-substituted benzyl radical continues to attack the liquid bromine to produce a dibrominated product and a bromine radical (this process is chain growth). Finally, the radical combines with the radical to complete the reaction (this process is chain termination), as shown below:

[0033]

[0034] The reaction mechanism of step S2 is: first, the amine captures the hydrogen on the phosphorus of diethyl phosphite to obtain a quaternary ammonium salt and a diethyl phosphite anion, the anion attacks one bromine in the dibromo substituent to obtain a bromine-substituted benzyl anion and diethyl bromophosphate, the bromine-substituted benzyl anion captures the hydrogen on the phosphorus of diethyl phosphite to obtain a monobromine-substituted product and a diethyl phosphite anion, and finally the diethyl phosphite anion attacks the diethyl bromophosphate to obtain (diethyl phosphate) (diethyl phosphoric anhydride), as shown below:

[0035]

[0036] The beneficial effects of the present invention are: the present invention has a reasonable design, a simple preparation method, and has the following advantages:

[0037] (1) In the present invention, step S1 and step S2 are combined into a one-pot process, which is simple to operate, reduces the separation of intermediates, and has a high yield;

[0038] (2) Step S2 of the present invention is carried out at room temperature and does not require special equipment; the post-processing adopts conventional liquid separation and drying operations, and the risk of process scale-up is low;

[0039] (3) The present invention avoids the use of precious metal catalysts or harsh conditions, and the raw materials (such as NBS and diethyl phosphite) are cheap and readily available, thus reducing production costs;

[0040] (4) The first solvent used in the present invention is green, environmentally friendly, cheap, readily available, and reusable, avoiding the use of highly toxic solvents (such as benzene), and the wastewater treatment is easy, meeting the requirements of green chemistry. In addition, the refined solvent is selected from a low-boiling point mixed system to reduce unit consumption and energy consumption;

[0041] (5) The product obtained by the present invention has high purity. Specifically, the purity of the obtained anastrozole intermediate is 95.22-98.29%, and the yield is 95.12-97.85%;

[0042] (6) The reaction conditions of each step of the present invention are mild, the post-processing process is standardized, and it is suitable for continuous production, providing a reliable source of intermediates for the large-scale preparation of anastrozole raw materials. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the specific embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0044] Figure 1 It is an intermediate dibromoan of anastrozole 1 H-NMR spectrum.

[0045] Figure 2 Anastrozole intermediate 1 H-NMR spectrum. DETAILED DESCRIPTION

[0046] It should be noted that the following detailed descriptions are illustrative and intended to provide further explanation of the present application. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present application belongs.

[0047] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments according to the present application. As used herein, unless the context clearly indicates otherwise, the singular also includes the plural. In addition, it should be understood that when the terms "comprise" and / or "include" are used in this specification, they indicate the presence of features, steps, operations, devices, components and / or combinations thereof.

[0048] The following will clearly and completely describe the technical solutions of the present invention in conjunction with the embodiments. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0049] A method for synthesizing anastrozole intermediate specifically comprises the following steps:

[0050] Step S1, using 3,5-bis[(2,2-dimethyl)acetylcyano]toluene as a raw material, adding a first solvent and mixing, and then adding N-bromobutylene imine to cause a substitution reaction to obtain a reaction mixture;

[0051] Step S2, adding diethyl phosphite and an organic base to the reaction mixture obtained in step S1 at room temperature, and reacting to obtain a finished reactant system;

[0052] The finished product reaction system obtained in step S3 and step S2 is post-treated to obtain a crude anastrozole intermediate;

[0053] Step S4: mixing the crude anastrozole intermediate obtained in step S3 with a refining solvent and refining the mixture to obtain a refined system; sequentially crystallizing and filtering the refined system to obtain a filter cake; and sequentially washing the filter cake (preferably with petroleum ether as the washing solvent) and drying the filter cake to obtain a finished anastrozole intermediate.

[0054] The finished product anastrozole intermediate prepared by the present invention is a white solid.

[0055] In step S1, the first solvent is selected from one or more of dichloromethane, dichloroethane, and tetrahydrofuran.

[0056] In step S1, the mass ratio of 3,5-bis[(2,2-dimethyl)acetylcyano]toluene to the first solvent is 1:(5-10), preferably 1:5; the molar ratio of 3,5-bis[(2,2-dimethyl)acetylcyano]toluene to N-bromobutyleneimide is 1:(1.2-2.0).

[0057] In step S1, the reaction temperature of the substitution reaction is 10 to 30° C., and the reaction time is 16 to 48 hours. The present invention uses TLC to monitor the reaction endpoint.

[0058] In step S2, the organic base is selected from one or more of 4-dimethylaminopyridine, N,N-diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0059] In step S2, the reaction time is 3 to 5 hours.

[0060] In step S3, the specific post-treatment operation is as follows: water (preferably purified water) is added to the finished reactant system obtained in step S2, the liquid is separated, the aqueous phase is extracted three times with DCM, the organic phases are combined, and the organic phase is washed twice with saturated NaHCO3 and saturated NaCl, dried over anhydrous Na2SO4, and concentrated to obtain a crude anastrozole intermediate.

[0061] In step S4, the mass ratio of the refined solvent to the crude anastrozole intermediate is (5-7):1.

[0062] In step S4, the refining solvent is selected from one or more of ethyl acetate, methyl tert-ether and petroleum ether. The refining solvent is preferably a mixture of ethyl acetate and petroleum ether, wherein the mass ratio of ethyl acetate to petroleum ether is 1:(10-20).

[0063] In step S4, the refining operation is carried out under reflux conditions, the refining temperature is 85-95° C., and the refining time is 1 hour.

[0064] In step S4, the crystallization temperature is 0-5°C, preferably 2-5°C.

[0065] In the present invention, unless otherwise specified, all raw material components are commercially available commodities well known to those skilled in the art.

[0066] Example 1

[0067] A method for synthesizing anastrozole intermediate, specifically:

[0068] In a 250mL three-necked flask, 3,5-bis[(2,2-dimethyl)acetylcyanide]toluene (23g, 0.10mol) and 115g of dichloromethane were added, and stirred for 10min. N-bromosuccinimide (27.1g, 0.15mol) was added. After the addition, the temperature was raised to 25°C and the reaction was kept warm for 24 hours. The reaction end point was monitored by TLC chromatography. DMAP (12.2g, 0.10mol) and diethyl phosphite (27.62g, 0.20mol) were added to the reaction system, and the reaction was kept warm at 25°C for 5 hours. Water was added to the system, and the liquids were separated. The aqueous phase was extracted twice with DCM. The organic phases were combined and washed with saturated NaHCO3 and NaCl. The organic phase was dried over anhydrous Na2SO4 and concentrated to dryness. 2 g of ethyl acetate and 30 g of petroleum ether were added to the filter cake in the residue. The temperature was raised to 90°C and stirred for 30 min. The insoluble material was filtered out, and the filtrate was cooled to 5°C. Crystallization occurred overnight, filtered, washed with petroleum ether, and dried in vacuo at 55°C to obtain anastrozole intermediate (white solid, 29.74 g, yield: 95.89%); HPLC purity: 96.396%.

[0069] The first solvent of Example 1 is dichloromethane (DCM), and the synthesis reaction of Example 1 is:

[0070]

[0071] Example 2

[0072] A method for synthesizing anastrozole intermediate, specifically:

[0073] In a 250mL three-necked flask, 3,5-bis[(2,2-dimethyl)acetylcyanide]toluene (23g, 0.10mol) and 115g tetrahydrofuran were added, and stirred for 10min. N-bromosuccinimide (27.1g, 0.15mol) was added. After the addition, the temperature was raised to 25°C and the reaction was kept warm for 26 hours. The reaction end point was monitored by TLC chromatography. DMAP (12.2g, 0.10mol) and diethyl phosphite (27.62g, 0.20mol) were added to the reaction system, and the reaction was kept warm at 25°C for 5 hours. Water was added to the system, and the liquids were separated. The aqueous phase was extracted twice with DCM. The organic phases were combined and washed with saturated NaHCO3 and NaCl. The organic phase was dried over anhydrous Na2SO4 and concentrated to dryness. 2 g of ethyl acetate and 30 g of petroleum ether were added to the filter cake in the residue. The temperature was raised to 90°C and stirred for 30 min. The insoluble material was filtered out, and the filtrate was cooled to 5°C. Crystallization occurred overnight, filtered, washed with petroleum ether, and dried in vacuo at 55°C to obtain anastrozole intermediate (white solid, 29.54 g, yield: 95.89%); HPLC purity: 95.326%.

[0074] The first solvent of Example 2 is tetrahydrofuran (THF), and the synthesis reaction of Example 2 is:

[0075]

[0076] Example 3

[0077] A method for synthesizing anastrozole intermediate, specifically:

[0078] In a 250mL three-necked flask, 3,5-bis[(2,2-dimethyl)acetylcyanide]toluene (23g, 0.10mol) and 115g of dichloromethane were added and stirred for 10min. N-bromosuccinimide (27.1g, 0.15mol) was added and the temperature was raised to 25°C. The reaction was kept warm for 24 hours. The end point of the reaction was monitored by TLC chromatography. DIPEA (12.9g, 0.10mol) and diethyl phosphite (27.62g, 0.20mol) were added to the reaction system. The reaction was kept warm at 25°C for 5 hours. Water was added to the reaction system, and the liquids were separated. The aqueous phase was extracted twice with DCM. The organic phases were combined and washed with saturated NaHCO3 and NaCl. The organic phase was dried over anhydrous Na2SO4 and concentrated to dryness. 2 g of ethyl acetate and 30 g of petroleum ether were added to the filter cake in the residue. The temperature was raised to 90°C and stirred for 30 min. The insoluble material was filtered out, and the filtrate was cooled to 5°C. Crystallization occurred overnight, filtered, washed with petroleum ether, and dried in vacuo at 55°C to obtain anastrozole intermediate (white solid, 30.35 g, yield: 97.85%); HPLC purity: 98.296%.

[0079] The organic base in Example 3 is N,N-diisopropylethylamine (DIPEA), and the synthesis reaction in Example 3 is:

[0080]

[0081] Example 4

[0082] A method for synthesizing anastrozole intermediate, specifically:

[0083] In a 250mL three-necked flask, 3,5-bis[(2,2-dimethyl)acetylcyanide]toluene (23g, 0.10mol) and 115g tetrahydrofuran were added, and stirred for 10min. N-bromosuccinimide (27.1g, 0.15mol) was added. After the addition, the temperature was raised to 25°C and the reaction was kept warm for 23 hours. The reaction end point was monitored by TLC chromatography. DBU (15.2g, 0.10mol) and diethyl phosphite (27.62g, 0.20mol) were added to the reaction system, and the reaction was kept warm at 25°C for 5 hours. Water was added to the system, and the liquids were separated. The aqueous phase was extracted twice with DCM. The organic phases were combined and washed with saturated NaHCO3 and NaCl. The organic phase was dried over anhydrous Na2SO4 and concentrated to dryness. 2 g of ethyl acetate and 30 g of petroleum ether were added to the filter cake in the residue. The temperature was raised to 90°C and stirred for 30 min. The insoluble material was filtered out, and the filtrate was cooled to 5°C. Crystallization occurred overnight, filtered, washed with petroleum ether, and dried in vacuo at 55°C to obtain anastrozole intermediate (white solid, 29.62 g, yield: 95.77%); HPLC purity: 95.416%.

[0084] The organic base in Example 4 is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The synthesis reaction of Example 4 is:

[0085]

[0086] Example 5

[0087] A method for synthesizing anastrozole intermediate, specifically:

[0088] In a 250mL three-necked flask, 3,5-bis[(2,2-dimethyl)acetylcyano]toluene (23g, 0.10mol) and 115g of dichloromethane were added, and stirred for 10min. N-bromosuccinimide (27.1g, 0.15mol) was added. After the addition, the temperature was lowered to 15°C and the reaction was kept warm for 24 hours. The reaction end point was monitored by TLC chromatography. DIPEA (12.9g, 0.10mol) and diethyl phosphite (27.62g, 0.20mol) were added to the reaction system, and the reaction was kept warm at 15°C for 5 hours. Water was added to the reaction system, and the liquids were separated. The aqueous phase was extracted twice with DCM. The organic phases were combined and washed with saturated NaHCO3 and NaCl. The organic phase was dried over anhydrous Na2SO4 and concentrated to dryness. 2 g of ethyl acetate and 30 g of petroleum ether were added to the filter cake in the residue. The temperature was raised to 90°C and stirred for 30 min. The insoluble material was filtered out, and the filtrate was cooled to 5°C. Crystallization occurred overnight, filtered, washed with petroleum ether, and dried in vacuo at 55°C to obtain anastrozole intermediate (white solid, 20.64 g, yield: 67.67%); HPLC purity: 96.166%.

[0089] After the addition of N-bromosuccinimide (27.1 g, 0.15 mol) in Example 5, the temperature was lowered to 15° C. The synthetic reaction of Example 5 was as follows:

[0090]

[0091] Example 6

[0092] A method for synthesizing anastrozole intermediate, specifically:

[0093] In a 250mL three-necked flask, 3,5-bis[(2,2-dimethyl)acetylcyano]toluene (23g, 0.10mol) and 115g of dichloromethane were added and stirred for 10min. N-bromosuccinimide (27.1g, 0.15mol) was added and the temperature was raised to 35°C. The reaction was kept warm for 24 hours. The end point of the reaction was monitored by TLC chromatography. DIPEA (12.9g, 0.10mol) and diethyl phosphite (27.62g, 0.20mol) were added to the reaction system. The reaction was kept warm at 35°C for 5 hours. Water was added to the reaction system, and the liquids were separated. The aqueous phase was extracted twice with DCM. The organic phases were combined and washed with saturated NaHCO3 and NaCl. The organic phase was dried over anhydrous Na2SO4 and concentrated to dryness. 2 g of ethyl acetate and 30 g of petroleum ether were added to the filter cake in the residue. The temperature was raised to 90°C and stirred for 30 min. The insoluble material was filtered out, and the filtrate was cooled to 5°C. Crystallization occurred overnight, filtered, washed with petroleum ether, and dried in vacuo at 55°C to obtain anastrozole intermediate (white solid, 18.64 g, yield: 61.11%); HPLC purity: 95.746%.

[0094] After the addition of N-bromosuccinimide (27.1 g, 0.15 mol) in Example 6, the temperature was raised to 35° C. The synthetic reaction of Example 6 was as follows:

[0095]

[0096] Example 7

[0097] A method for synthesizing anastrozole intermediate, specifically:

[0098] In a 250mL three-necked flask, 3,5-bis[(2,2-dimethyl)acetylcyanide]toluene (23g, 0.10mol) and 92g of dichloromethane were added and stirred for 10min. N-bromosuccinimide (27.1g, 0.15mol) was added and the temperature was raised to 25°C. The reaction was kept warm for 24 hours. The reaction end point was monitored by TLC chromatography. DIPEA (12.9g, 0.10mol) and diethyl phosphite (27.62g, 0.20mol) were added to the reaction system. The reaction was kept warm at 25°C for 5 hours. Water was added to the system, and the liquids were separated. The aqueous phase was extracted twice with DCM. The organic phases were combined and washed with saturated NaHCO3 and NaCl. The organic phase was dried over anhydrous Na2SO4 and concentrated to dryness. 2 g of ethyl acetate and 30 g of petroleum ether were added to the filter cake in the residue. The temperature was raised to 90°C and stirred for 30 min. The insoluble material was filtered out, and the filtrate was cooled to 5°C. Crystallization occurred overnight, filtered, washed with petroleum ether, and dried in vacuo at 55°C to obtain anastrozole intermediate (white solid, 27.84 g, yield: 90.30%); HPLC purity: 96.218%.

[0099] In Example 7, the amount of dichloromethane (DCM) added was 92 g; the synthetic reaction of Example 7 was:

[0100]

[0101] Example 8

[0102] A method for synthesizing anastrozole intermediate, specifically:

[0103] In a 250mL three-necked flask, 3,5-bis[(2,2-dimethyl)acetylcyanide]toluene (23g, 0.10mol) and 184g of dichloromethane were added and stirred for 10min. N-bromosuccinimide (27.1g, 0.15mol) was added and the temperature was raised to 35°C. The reaction was kept warm for 24 hours. The reaction end point was monitored by TLC chromatography. DIPEA (12.9g, 0.10mol) and diethyl phosphite (27.62g, 0.20mol) were added to the reaction system. The reaction was kept warm at 35°C for 5 hours. Water was added to the reaction system, the liquids were separated, the aqueous phase was extracted twice with DCM, the organic phases were combined, and the mixture was washed with saturated NaHCO3 and NaCl. The organic phase was dried over anhydrous Na2SO4 and concentrated to dryness. To the filter cake in the residue were added 2 g of ethyl acetate and 30 g of petroleum ether. The temperature was raised to 90°C and stirred for 30 min. The insoluble material was filtered out, and the filtrate was cooled to 5°C. Crystallization occurred overnight, filtered, washed with petroleum ether, and dried in vacuo at 55°C to obtain anastrozole intermediate (white solid, 29.44 g, yield: 97.48%); HPLC purity: 96.374%.

[0104] In Example 8, the amount of dichloromethane (DCM) added was 182 g; the synthetic reaction of Example 8 was:

[0105]

[0106] Figure 1 It is an intermediate dibromoan of anastrozole 1 In the H-NMR spectrum, there are 5 groups of peaks: the solvent peak at δ = 7.25, the peaks at δ = 7.64 and δ = 7.53 are the peaks of the three hydrogens on the benzene ring in the impurity structure, the peak at δ = 6.66 is the peak of the hydrogen on the benzyl group, and the peak at δ = 1.78 is the peak of the four methyl groups; therefore, the NMR data is 1 H NMR (500MHz, CDCl3): δ7.64 (d, J=1.9Hz, 2H), 7.53 (t, J=1.8Hz, 1H), 6.66 (s, 1H), 1.78 (s, 12H). Figure 1 It can be proved that what was prepared was anastrozole EP impurity D.

[0107] Figure 2 Anastrozole intermediate 1 In the H-NMR spectrum, there are four groups of peaks: the solvent peak at δ = 5.25, the peak at δ = 7.5 is the peak of the three hydrogens on the benzene ring in the structure of the anastrozole intermediate, the peak at δ = 4.56 is the peak of the hydrogen on the benzyl group, and the peak at δ = 1.78 is the peak of the four methyl groups; therefore, the NMR data is 1 H NMR (400MHz, CD2Cl2): δ7.50 (dt, J=6.6, 1.9Hz, 3H), 4.56 (d, J=2.5Hz, 2H), 1.76 (d, J=2.5Hz, 12H). Figure 2 It can be proved that what is prepared is anastrozole intermediate.

[0108] Comparative Example 1

[0109] The conventional method for preparing anastrozole intermediate is as follows:

[0110] In a 250mL three-necked flask, 3,5-bis[(2,2-dimethyl)acetylcyano]toluene (23g, 0.10mol) and 115g of dichloromethane were added and stirred for 10min. N-bromosuccinimide (27.1g, 0.15mol) was added and the temperature was raised to 25°C. The reaction was kept warm for 24 hours. The end point of the reaction was monitored by TLC chromatography. Water was added to the reaction system, the liquids were separated, the aqueous phase was extracted twice with DCM, the organic phases were combined, and washed with saturated NaHCO3 and NaCl. The organic phase was washed with anhydrous HCl. The mixture was dried over Na2SO4 and concentrated to dryness. 2 g of ethyl acetate and 30 g of petroleum ether were added to the filter cake in the residue. The temperature was raised to 90°C and stirred for 30 min. The insoluble matter was filtered out. The filtrate was cooled to 5°C and crystallized overnight. The mixture was filtered off with suction, washed with petroleum ether, and dried in vacuo at 55°C to obtain a mixture of anastrozole intermediate and anastrozole intermediate dibromide (white solid). After column separation, anastrozole intermediate (white solid, 17.23 g) and anastrozole intermediate dibromide (white solid, 12.94 g) were obtained.

[0111] The synthetic reaction of Comparative Example 1 is:

[0112]

[0113] Comparative Example 1 does not convert the dibromo product into anastrozole intermediate by adding diethyl phosphite and an organic base, resulting in low raw material utilization and high production cost.

[0114] In summary, the present invention uses 3,5-bis[(2,2-dimethyl)acetylcyanide]toluene as a raw material, and undergoes a substitution reaction with N-bromobutyleneimide (NBS) in a suitable solvent to generate a mixture containing an anastrozole intermediate and a dibromide; subsequently, by adding diethyl phosphite and an organic base, the dibromide is converted into an anastrozole intermediate. This synthesis method improves the utilization rate of the raw material 3,5-bis[(2,2-dimethyl)acetylcyanide]toluene and the yield of the anastrozole intermediate, thereby reducing production costs.

[0115] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for synthesizing anastrozole intermediate, characterized in that: The specific steps include: Step S1, using 3,5-bis[(2,2-dimethyl)acetylcyano]toluene as a raw material, adding a first solvent and mixing, and then adding N-bromobutylene imine to cause a substitution reaction to obtain a reaction mixture; Step S2, adding diethyl phosphite and an organic base to the reaction mixture obtained in step S1 at room temperature, and reacting to obtain a finished reactant system; The finished product reaction system obtained in step S3 and step S2 is post-treated to obtain a crude anastrozole intermediate; Step S4: mixing the crude anastrozole intermediate obtained in step S3 with a refining solvent and refining the mixture to obtain a refined system; sequentially crystallizing and filtering the refined system to obtain a filter cake; and sequentially washing and drying the filter cake to obtain a finished anastrozole intermediate.

2. The method for synthesizing an anastrozole intermediate according to claim 1, wherein: In step S1, the first solvent is selected from one or more of dichloromethane, dichloroethane, and tetrahydrofuran.

3. The method for synthesizing an anastrozole intermediate according to claim 1, wherein: In step S1, the mass ratio of 3,5-bis[(2,2-dimethyl)acetylcyano]toluene to the first solvent is 1:(5-10), and the molar ratio of 3,5-bis[(2,2-dimethyl)acetylcyano]toluene to N-bromobutyleneimide is 1:(1.2-2.0).

4. The method for synthesizing an anastrozole intermediate according to claim 1, wherein: In step S1, the reaction temperature of the substitution reaction is 10-30° C., and the reaction time is 16-48 hours.

5. The method for synthesizing an anastrozole intermediate according to claim 1, wherein: In the step S2, the organic base is selected from one or more of 4-dimethylaminopyridine, N,N-diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene.

6. The method for synthesizing an anastrozole intermediate according to claim 1, wherein: In step S2, the reaction time is 3 to 5 hours.

7. The method for synthesizing an anastrozole intermediate according to claim 1, wherein: In step S3, the specific post-treatment operation is as follows: adding water to the finished reactant system obtained in step S2, separating the liquids, extracting the aqueous phase with DCM three times, combining the organic phases, washing the organic phases with saturated NaHCO3 and saturated NaCl twice each, drying over anhydrous Na2SO4, and concentrating to obtain a crude anastrozole intermediate.

8. The method for synthesizing an anastrozole intermediate according to claim 1, wherein: In step S4, the refining solvent is selected from one or more of ethyl acetate, methyl tert-ether and petroleum ether.

9. The method for synthesizing an anastrozole intermediate according to claim 1, wherein: In the step S4, the refining operation is carried out under reflux conditions, the refining temperature is 85-95° C., and the refining time is 1 hour.

10. The method for synthesizing an anastrozole intermediate according to claim 1, wherein: In the step S4, the crystallization temperature is 0-5°C.

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