Compound as well as preparation method and application thereof

Abstract

The invention relates to a compound as well as a preparation method and application thereof. The preparation method comprises the following steps: by taking a compound 1 and thiourea as starting raw materials, sequentially carrying out three-step reaction of nucleophilic substitution, alkaline hydrolysis and secondary nucleophilic substitution. The invention provides a synthetic route of the compound for the first time, and solves the technical problem of lack of a standard substance of the compound for a long time. The prepared standard substance can be used for establishing a monitoring analysis method for the key impurity in a fulvestrant production process, and has important significance for improving the quality of fulvestrant bulk drugs. The method has the advantages of mild conditions and safe operation, avoids the use of high-risk reagents, and is suitable for the preparation of standard substances.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical synthesis technology, specifically relating to a compound, its preparation method, and its application. Background Technology

[0002] Fulvestrant is a novel estrogen receptor antagonist widely used to treat hormone receptor-positive advanced breast cancer. In the chemical synthesis process of fulvestrant, compound 1 (see appendix...) Figure 2 Compound 1 is an important intermediate. However, during the preparation of compound 1 or subsequent reactions, it may undergo side reactions with sulfur-containing reagents such as thiourea used in the process, generating a structurally similar thioether impurity, which is the target compound of this invention.

[0003] The presence of this thioether impurity not only affects the purity of the main product, fulvestrant, but more seriously, it may be oxidized in subsequent processes to generate sulfoxide or sulfone impurities that are more difficult to remove. These oxidation products will ultimately remain in the active pharmaceutical ingredient, seriously affecting the quality and safety of the drug. Therefore, strict monitoring of thioether impurities in intermediates is crucial. Monitoring requires the availability of high-purity standards for this impurity to establish accurate and sensitive analytical methods.

[0004] Currently, the structure of this specific thioether impurity is not disclosed in existing technologies, nor are there any reports on its synthesis methods. The lack of effective synthetic methods to obtain a standard of this impurity has become a key technical bottleneck in optimizing the synthesis process of fulvestrant and improving the quality of its active pharmaceutical ingredient. Summary of the Invention

[0005] On the one hand, the present invention provides a novel fulvestrant intermediate impurity with the following structural formula: .

[0006] Secondly, to overcome the gaps in the existing technology, this invention provides a method for preparing fulvestrant intermediate impurities that is rationally planned, easy to operate, has good yield, and high purity, thereby solving the problem of the inability to obtain reference standards for this impurity and providing a key material basis for the quality control of fulvestrant active pharmaceutical ingredient.

[0007] The process route of this invention is as follows:

[0008] The technical solution of this invention is implemented as follows: S1. Compound 1 and thiourea are dissolved in an organic solvent and reacted to obtain intermediate 2; S2. Intermediate 2 is reacted under alkaline conditions to obtain intermediate 3; S3. Dissolve intermediate 3 and compound 1 in an organic solvent and react under alkaline conditions to obtain the compound product.

[0009] Based on the above technical solution, preferably, in step S1, compound 1 and thiourea are added to an organic solvent, heated to 78°C and reacted for 18 h. After the reaction is complete, the reaction solution is concentrated under reduced pressure to obtain intermediate 2.

[0010] More preferably, in step S1, taking into account the solubility of compound 1 and thiourea, the organic solvent is ethanol or methanol.

[0011] More preferably, in step S1, the molar ratio of compound 1 to thiourea is 1:1.2~2, preferably 1:1.5. Too little thiourea will cause compound 1 to not react completely, affecting the yield and purity, while too much thiourea will result in waste.

[0012] In a further preferred embodiment, in step S1, considering the solubility of compound 1 and thiourea, if the solvent is too small, compound 1 and thiourea cannot be completely dissolved, and if the solvent is too large, there will be waste and the reaction rate will be affected. The mass-volume ratio (g / mL) of compound 1 and organic solvent is 1:5~20, preferably 1:10.

[0013] Based on the above technical solution, preferably, in step S2, intermediate 2 is dissolved in an organic solvent, and sodium hydroxide aqueous solution is slowly added dropwise while controlling the temperature at 0~10℃. After the addition is complete, the temperature is raised to react for 2 hours. After the reaction is complete, intermediate 3 is obtained by extraction, water washing, vacuum concentration, and column chromatography purification.

[0014] More preferably, in steps S2 and S3, considering the solubility of intermediate 2 and intermediate 3, the organic solvents are both N,N-dimethylformamide or dimethyl sulfoxide.

[0015] More preferably, in steps S2 and S3, the reagents used for the alkaline conditions are sodium hydroxide or potassium hydroxide.

[0016] In a further preferred embodiment, in step S2, the molar ratio of intermediate 2 to sodium hydroxide is 1:1 to 5. If the amount of sodium hydroxide used is too small, there will be some raw material left over. At the same time, the reaction time is too long, and if the amount of sodium hydroxide used is too large, there will be waste.

[0017] More preferably, in step S2, considering the solubility of intermediate 2 and the alkali, the mass-volume ratio (g / mL) of intermediate 2, N,N-dimethylformamide and water is 1:4~7:0.5~2, preferably 1:5:1.

[0018] In a further preferred embodiment, in step S2, the reaction temperature is 20~100℃, and considering the safety of the reaction, room temperature is selected, preferably 25~35℃.

[0019] Based on the above technical solution, preferably, in step S3, intermediate 3 and compound 1 are dissolved in an organic solvent, and sodium hydroxide aqueous solution is slowly added dropwise while controlling the temperature at 0~10℃. After the addition is complete, the temperature is raised to react for 2 hours. After the reaction is complete, the compound is obtained by extraction, washing with water, concentration under reduced pressure, and preparative liquid phase purification.

[0020] More preferably, in step S3, the molar ratio of intermediate 3, compound 1, and sodium hydroxide is 1:1~2:7~14, preferably 1:1:10.

[0021] More preferably, in step S3, the mass-to-volume ratio (g / mL) of intermediate 3, N,N-dimethylformamide, and water is 1:5~15:4~7, preferably 1:10:5.

[0022] More preferably, in step S3, the reaction temperature is 20~80℃, and more preferably 30~35℃.

[0023] Thirdly, the compound is used as a standard for impurity detection in the fulvestrant production process.

[0024] The beneficial effects of this invention are as follows: (1) For the first time, a fully chemical synthesis route for the specific synthesis of this impurity was successfully designed and implemented, filling a technological gap; it provided an essential material basis for establishing a sound quality control method for fulvestrant raw materials and their preparations, and directly supported the compliant registration and safe use of drugs.

[0025] (2) The preparation method of the present invention has mild reaction conditions, low raw material and production costs, does not involve high-risk reagents, and has high production safety.

[0026] (3) The post-processing procedure was simplified, the purification cost and difficulty were reduced, and high-purity products (HPLC purity > 96%) were successfully obtained. Attached Figure Description

[0027] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0028] Figure 1 The structural formula of the compound described in this invention is as follows; Figure 2 This is a process flow diagram of the preparation method of the present invention; Figure 3 This is the HPLC chromatogram of the fulvestrant intermediate impurity in Example 1 of the present invention; Figure 4 The MS spectrum of the fulvestrant intermediate impurity positive ion in Example 1 of this invention; Figure 5 For the intermediate impurities of fulvestrant in Example 1 of this invention 1 HNMR spectrum; Figure 6 This is the HPLC chromatogram of the intermediate in the industrial production of fulvestrant. The peak at a relative retention time of 1.170 represents the impurity in the fulvestrant intermediate. Detailed Implementation

[0029] Depend on Figure 6 As shown, a small chromatographic peak appeared at a retention time of 1.170 on HPLC during the industrial production of the intermediate preceding fulvestrant. This peak is the target compound to be prepared and controlled in this invention.

[0030] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0031] Table 1: Material Source Description Table

[0032] Example 1: S1, compound 1 (10.00 g), and thiourea (2.39 g) were added to ethanol (100 mL), stirred and heated to 78 °C for 18 h. After the reaction was complete as monitored by TLC, the reaction solution was directly concentrated under reduced pressure to obtain intermediate 2 (14.50 g).

[0033] S2 and intermediate 2 (12.50 g) were added to N,N-dimethylformamide (60 mL), stirred until dissolved, and sodium hydroxide aqueous solution (3.45 g sodium hydroxide dissolved in 12 mL water) was added dropwise while controlling the temperature at 0-10℃. The reaction was carried out at 30℃ for 2 h. After the reaction was completed by TLC monitoring, water was added to the reaction solution, and ethyl acetate was added for extraction. The organic phase was washed once with water, concentrated under reduced pressure to dryness, and then purified by column chromatography to obtain intermediate 3 (4.80 g).

[0034] S3, intermediate 3 (3.45 g), and compound 1 (3.83 g) were added to N,N-dimethylformamide (35 mL), stirred until dissolved, and sodium hydroxide aqueous solution (3.20 g sodium hydroxide dissolved in 17 mL water) was added dropwise while controlling the temperature at 0-10℃. The reaction was carried out at 30℃ for 2 h. After the reaction was completed by TLC monitoring, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed once with water and concentrated to dryness under reduced pressure. The solution was then purified by column chromatography to obtain the target compound, i.e., the fulvestrant intermediate impurity (5.20 g), with a yield of 47.6% and an HPLC purity of 96.795%.

[0035] ESI-LCMS (m / z): 809.8 1 H NMR (600 MHz, DMSO-d6) δ ppm 0.66 (m, 6 H) 0.88-0.91 (m, 2 H) 1.14-1.36 (m, 36 H) 1.45-1.49 (m, 8 H) 1.64-1.65 (br d, J=9.39 Hz, 2 H) 1.77-1.79(br d, J=12.33 Hz, 2 H) 1.84-1.90 (m, 2 H) 2.14-2.18 (br t, J=11.44 Hz, 2 H)2.22-2.25 (m, 2 H) 2.41-2.44 (m, 4 H) 2.57-2.60 (m, 2 H) 2.72-2.76 (br dd, J=16.43, 4.70 Hz, 2 H) 3.50-3.54 (td, J=8.36, 4.99 Hz, 2 H) 4.48-4.49 (m, 2 H)6.40-6.41 (m, 2 H) 6.48-6.50 (m, 2 H) 7.02-7.04 (m, 2 H) 8.96 (m, 2 H).

[0036] Example 2: S1, compound 1 (10.00 g), and thiourea (2.07 g) were added to ethanol (100 mL), stirred and heated to 78 °C for 18 h. After the reaction was complete as monitored by TLC, the reaction solution was directly concentrated under reduced pressure to obtain intermediate 2 (13.97 g).

[0037] S2 and intermediate 2 (13.97 g) were added to N,N-dimethylformamide (84 mL), stirred until dissolved, and sodium hydroxide aqueous solution (3.13 g sodium hydroxide dissolved in 8 mL water) was added dropwise at 0-10℃. The reaction was carried out at 35℃ for 2 h. After the reaction was complete as monitored by TLC, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed once with water, concentrated under reduced pressure to dryness, and then purified by column chromatography to obtain intermediate 3 (4.71 g).

[0038] S3, intermediate 3 (4.71 g), and compound 1 (7.83 g) were added to N,N-dimethylformamide (28 mL), stirred until dissolved, and sodium hydroxide aqueous solution (3.50 g sodium hydroxide dissolved in 19 mL water) was added dropwise at 0-10 °C. The reaction was carried out at 25 °C for 2 h. After the reaction was complete as monitored by TLC, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed once with water and concentrated to dryness under reduced pressure. The solution was then purified by column chromatography to obtain the target compound, i.e., the fulvestrant intermediate impurity (6.53 g), with a yield of 37.7%.

[0039] Example 3: S1, compound 1 (10.00 g), and thiourea (2.87 g) were added to ethanol (100 mL), stirred and heated to 78 °C for 18 h. After the reaction was complete as monitored by TLC, the reaction solution was directly concentrated under reduced pressure to obtain intermediate 2 (15.14 g).

[0040] S2 and intermediate 2 (15.14 g) were added to N,N-dimethylformamide (70 mL), stirred until dissolved, and sodium hydroxide aqueous solution (3.83 g sodium hydroxide dissolved in 10 mL water) was added dropwise at 0-10℃. The reaction was carried out at 25℃ for 2 h. After the reaction was completed by TLC monitoring, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed once with water, concentrated under reduced pressure to dryness, and then purified by column chromatography to obtain intermediate 3 (4.93 g).

[0041] S3, intermediate 3 (4.93 g), and compound 1 (7.10 g) were added to N,N-dimethylformamide (60 mL), stirred until dissolved, and sodium hydroxide aqueous solution (3.43 g sodium hydroxide dissolved in 25 mL water) was added dropwise at 0-10 °C. The reaction was carried out at 40 °C for 2 h. After the reaction was complete as monitored by TLC, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed once with water, concentrated under reduced pressure to dryness, and then purified by column chromatography to obtain the target compound, i.e., the fulvestrant intermediate impurity (6.15 g), with a yield of 35.5%.

[0042] Application Example 4: The HPLC detection method for fulvestrant intermediate impurities described in this invention is as follows: A NanoChromChromcore 120C8 3µm, 4.6*150mm column was used; purified water was used as mobile phase A, and acetonitrile as mobile phase B; the detector wavelengths were 205nm and 240nm; the mobile phase flow rate was 1.0mL / min; the column temperature was 40℃; the injection volume was 5µL; and mobile phases A and B were eluted linearly according to Table 2. An appropriate amount of the sample was dissolved in acetonitrile to prepare a 1mg / mL solution for injection.

[0043] Table 2 Gradient elution program table

[0044] The method for removing the fulvestrant intermediate impurity described in this invention is as follows: after synthesizing the fulvestrant intermediate into fulvestrant, the impurity is removed by recrystallization from ethyl acetate.

[0045] The method for removing impurities from the fulvestrant intermediate described in this invention is as follows: after synthesizing the fulvestrant intermediate into fulvestrant, it is removed by recrystallization from ethyl acetate. The above description is merely a preferred embodiment of this invention and is not intended to limit the invention. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of this invention should be included within the scope of protection of this invention.

Claims

1. A compound, characterized in that, The structural formula is as follows: 。 2. The method for preparing the compound according to claim 1, characterized in that, The method comprises the following steps: S1, dissolving compound 1 and thiourea in an organic solvent to obtain intermediate 2; S2, reacting intermediate 2 under alkaline conditions to obtain intermediate 3; S3, dissolving intermediate 3 and compound 1 in an organic solvent and reacting under alkaline conditions to obtain the compound product; The structural formula of the compound 1, intermediate 2 and intermediate 3 is as follows: 。 3. The production method according to claim 2, wherein In step S1, the organic solvent is ethanol or methanol.

4. The production method according to claim 2, wherein In step S1, the molar ratio of compound 1 to thiourea is 1:1.2-2.

5. The production method according to claim 2, wherein In steps S2 and S3, the reagent used under the alkaline condition is sodium hydroxide or potassium hydroxide.

6. The production method according to claim 2, wherein In step S2, the molar ratio of intermediate 2 to the reagent used under the alkaline condition is 1:1-5.

7. The production method according to claim 2, wherein In steps S2 and S3, the organic solvent is N,N-dimethylformamide or dimethyl sulfoxide.

8. The production method according to claim 2, wherein In step S3, the molar ratio of intermediate 3, compound 1 and the reagent used under the alkaline condition is 1:1-2:7-14.

9. The production method according to claim 2, wherein In step S3, intermediate 3 and compound 1 are dissolved in an organic solvent, sodium hydroxide aqueous solution is added under temperature control of 0-10 DEG C, and then the temperature is raised to 20-80 DEG C.

10. Use of the compound of claim 1 or the compound obtained by the preparation method of any one of claims 2-9 as a standard for detecting an impurity in a production process of a raw material of fulvestrant.

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