A process for the preparation of a toremifene citrate intermediate

Abstract

The application relates to the technical field of compound synthesis, and particularly discloses a preparation method of an intermediate of toripalimab citrate, which comprises the following steps: a first reaction of cinnamyl alcohol and diethyl phosphite in an organic solvent to obtain a first reactant; and a second reaction of the obtained first reactant, alkali and 4-[2-(N,N-dimethylamino)ethoxy]benzophenone to obtain a second reactant containing the intermediate I of toripalimab citrate. A brand-new process route is developed, raw materials used in the route are all easy to obtain, the whole reaction route is short, operation is simple, reaction conditions are mild and safe, the yield of the obtained intermediate I of toripalimab citrate is high, the purity is also high, the total yield is more than 80%, the purity is more than 99.9%, and industrial production can be realized.

Description

Technical Field

[0001] This invention relates to the field of compound synthesis technology, and specifically to a method for preparing toremifene citrate intermediate. Background Technology

[0002] Breast cancer is one of the leading causes of cancer-related deaths among women worldwide, with approximately 60%-70% being estrogen receptor-positive (ER+) subtypes. Endocrine therapy is a core approach for adjuvant therapy and palliative care in advanced stages for these patients. Toremifene citrate, a second-generation selective estrogen receptor modulator (SERM), was originally developed by Farmos in Finland and first marketed in Finland in 1988. It was approved by the US FDA in 1997 and is clinically used for the treatment of postmenopausal women with ER+ or unknown metastatic breast cancer. It is also widely used as adjuvant endocrine therapy in premenopausal patients. Toremifene citrate has become a first-line endocrine drug recommended by domestic and international breast cancer guidelines, and its clinical demand and market size are showing a stable and rapid growth trend.

[0003] Currently, there is only one reported route for the industrial-scale preparation of toremifene citrate. Starting with 4-[2-(N,N-dimethylamino)ethoxy]benzophenone and cinnamaldehyde, a condensation and reduction reaction occurs simultaneously under the action of lithium aluminum hydride as a reducing agent to obtain the intermediate triarylbutanediol. Triarylbutanediol is then subjected to high-temperature acidic conditions to remove the tertiary carbon hydroxyl group and introduce a double bond to obtain the key intermediate (Z)-triarylbutenol. Finally, the hydroxyl group of (Z)-triarylbutenol reacts with a chlorination reagent to obtain toremifene, which is then salted with citric acid to obtain toremifene citrate.

[0004]

[0005] Although the aforementioned mature industrialization route has been applied for many years, many prominent problems still exist in actual production: The first step of the route requires the use of lithium aluminum hydride (LiAlH4), which is extremely flammable and explosive when exposed to water and moisture, and it is difficult to find safer alternative reagents. The safety risks of material storage and production process are extremely high. The yield of the first step is highly sensitive to the quality of LiAlH4. Fresh reagent can result in a yield of over 90%, while if some of it decomposes and becomes inactive due to moisture, the yield will drop sharply to below 60%. In the second step of dehydration to generate the key intermediate (Z)-triarylbutenol, a mixture of Z / E configurations with similar proportions will be produced. However, the pharmaceutically effective configuration is the Z type, which requires high-temperature transposition under acidic conditions for more than 48 hours to convert the excess E type into the Z type. This process is time-consuming, energy-intensive, and has poor environmental friendliness, significantly increasing production costs.

[0006] There is an urgent clinical and market demand for high-purity, low-cost, and environmentally friendly toremifene citrate raw materials. To overcome the aforementioned technical bottlenecks and meet the requirements for high-quality, low-cost, and green drug production, this invention addresses the shortcomings of existing industrial production processes by developing a novel method for preparing the key intermediate (Z)-triarylbutenol with high stereoselectivity, high yield, and high production safety. This method enables the efficient, safe, and green synthesis of toremifene citrate, providing high-quality and economical raw materials for clinical use, enhancing the market competitiveness of domestically produced drugs, and promoting the industrialization and technological upgrading of endocrine therapy drugs for breast cancer. Summary of the Invention

[0007] Purpose of the invention: The technical problem to be solved by the present invention is to provide a method for preparing the intermediate (Z)-triarylbutenol of toremifene citrate, which is inadequate for the prior art.

[0008] To address the aforementioned technical problems, this invention discloses a method for preparing the toremifene citrate intermediate (Z)-triarylbutenol.

[0009] In some embodiments, the preparation method includes the following steps: cinnamyl alcohol and diethyl phosphite undergo a first reaction in an organic solvent to obtain a first reactant containing intermediate II; the obtained first reactant undergoes a second reaction with a base and 4-[2-(N,N-dimethylamino)ethoxy]benzophenone to obtain a second reactant containing toremifene citrate intermediate I; wherein intermediate I is (Z)-triarylbutenol; the reaction route is shown below:

[0010] .

[0011] The first reaction is an olefin addition reaction occurring in an organic solvent upon heating to generate intermediate II; in the second reaction, intermediate II reacts with a base in situ to generate a phosphonate carbanion intermediate, which directly reacts with 4-[2-(N,N-dimethylamino)ethoxy]benzophenone in a Horner–Wadsworth–Emmons reaction to generate toremifene citrate intermediate I.

[0012] In some embodiments, the molar ratio of cinnamyl alcohol to diethyl phosphite is 1:0.9-1.3, and in some embodiments it is 1:1.1.

[0013] In some embodiments, the organic solvent is 1,4-dioxane and / or tetrahydrofuran, and in some preferred embodiments, it is 1,4-dioxane.

[0014] In some embodiments, the mass-to-volume ratio of cinnamyl alcohol to organic solvent is 90-110 g / L, and in some embodiments it is 100 g / L.

[0015] In some embodiments, the temperature of the first reaction is 60-110°C, and in some embodiments it is 60-100°C.

[0016] In some embodiments, the duration of the first reaction is 2-3 hours.

[0017] In some embodiments, the first reactant is not separated and purified, but directly reacted with a base and 4-[2-(N,N-dimethylamino)ethoxy]benzophenone in a second reaction.

[0018] In some embodiments, the base is sodium hydride and / or potassium tert-butoxide; in some embodiments, the sodium hydride is added to the reaction system in the form of 60% sodium hydride; and in some preferred embodiments, the base is potassium tert-butoxide.

[0019] In some embodiments, the molar ratio of cinnamyl alcohol to the base and 4-[2-(N,N-dimethylamino)ethoxy]benzophenone is 1:0.9-1.3:0.7-1.1, and in some embodiments it is 1:1.1:0.9.

[0020] In some embodiments, the temperature of the second reaction is 20-30°C.

[0021] In some embodiments, the second reaction takes 4-5 hours.

[0022] In some embodiments, after the second reaction is completed, the organic solvent is removed by vacuum distillation of the obtained second reactant, water is added to the residue and stirred, and the mixture is filtered for the first time to obtain a first filter cake; water and ethanol are added to the obtained first filter cake, the mixture is dissolved and cooled, and then filtered for the second time to obtain a second filter cake. The obtained second filter cake is toremifene citrate intermediate I.

[0023] This invention provides a novel method for preparing (Z)-triarylbutenol. This method has a simple route, mild reaction conditions, is safe and easy to operate, and produces high configuration purity. It is suitable for the large-scale industrial production of high-purity, green toremifene citrate raw materials. It can solve the problems of high safety risks, low configuration purity, and time-consuming and energy-intensive configuration conversion in the preparation of (Z)-triarylbutenol, the key intermediate of toremifene citrate, in the existing technology.

[0024] Beneficial effects: Compared with the prior art, the advantages of the present invention are as follows:

[0025] This invention develops a novel process route. The raw and auxiliary materials used in this route are readily available, stable, easy to store, inexpensive, and in ample supply. Most importantly, the entire reaction route is short, simple to operate, and the reaction conditions are mild and safe, conforming to the concept of green chemistry. The resulting product (Z)-triarylbutenol has a high yield, with an overall yield of over 80% based on 4-[2-(N,N-dimethylamino)ethoxy]benzophenone, and a purity of up to 99.9%. No E-configuration impurities were detected, which is conducive to realizing industrial production. Attached Figure Description

[0026] Figure 1 The image shows the HRMS spectrum of (Z)-triarylbutenol obtained in Example 1 of this invention.

[0027] Figure 2 The (Z)-triarylbutenol obtained in Example 1 of this invention 1 H-NMR spectrum.

[0028] Figure 3 The HPLC spectrum of (Z)-triarylbutenol obtained in Example 1 of this invention is shown. Detailed Implementation

[0029] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.

[0030] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; unless otherwise specified, the reagents and materials are commercially available.

[0031] Example 1:

[0032] At room temperature, 100.0 g (745.28 mmol) cinnamyl alcohol, 113.2 g (819.81 mmol) diethyl phosphite, and 1 L of 1,4-dioxane were added to a reaction vessel. After the addition was complete, the mixture was heated to 100 °C with stirring and reacted for 3 h. The system was then cooled to below 20 °C, and 92.0 g (819.81 mmol) potassium tert-butoxide and 180.7 g (670.75 mmol) 4-[2-(N,N-dimethylamino)ethoxy]benzophenone were added. After the addition was complete, the mixture was stirred at 20-30 °C for 5 h. 1,4-Dioxane was removed by vacuum distillation. 500 mL of purified water was added to the residue, and the mixture was stirred at room temperature for 30 min. After filtration, 900 mL of ethanol and 300 mL of purified water were added to the filter cake. The mixture was heated until dissolved, then slowly cooled to 10-20℃, filtered, and the filter cake was dried to obtain 223.5 g of (Z)-triarylbutenol, with a yield of 86% and a purity of 99.9494%. NMR spectroscopy was performed as follows: Figure 1and Figure 2 As shown.

[0033] HRMS (ESI) found 388.2254 [M+H] + .

[0034] 1 H NMR (400 MHz, CDCl3): δ = 7.35 – 7.13 (m, 10H), 6.78 (d, J = 8.8 Hz,2H), 6.56 (d, J = 8.4 Hz, 2H), 3.92 (t, J = 6.0 Hz, 2H), 3.57 (t, J = 6.8 Hz,2H), 2.74 (t, J = 6.8 Hz, 2H), 2.63 (t, J = 6.0 Hz, 2H), 2.27 (s, 6H), 1.59(br, 1H).

[0035] The obtained (Z)-triarylbutenol was analyzed using HPLC area normalization method, such as... Figure 3 As shown, no E-configuration impurities were detected.

[0036] Example 2:

[0037] At room temperature, 100.0 g (745.28 mmol) cinnamyl alcohol, 113.2 g (819.81 mmol) diethyl phosphite, and 1 L tetrahydrofuran were added to a reaction vessel. After the addition was complete, the mixture was heated to 60 °C with stirring and reacted for 3 h. The system was then cooled to below 20 °C, and 92.0 g (819.81 mmol) potassium tert-butoxide and 180.7 g (670.75 mmol) 4-[2-(N,N-dimethylamino)ethoxy]benzophenone were added. After the addition was complete, the mixture was stirred at 20-30 °C for 5 h. The tetrahydrofuran was removed by vacuum distillation, and 500 mL of purified water was added to the residue. The mixture was stirred at room temperature for 30 min, filtered, and 900 mL of ethanol and 300 mL of purified water were added to the filter cake. The mixture was heated to dissolve the residue, then slowly cooled to 10-20 °C, filtered, and the filter cake was dried to give 210.5 g of (Z)-triarylbutenol, with a yield of 81%.

[0038] Example 3:

[0039] The preparation method of (Z)-triarylbutenol in this embodiment is as follows:

[0040] At room temperature, 100.0 g (745.28 mmol) cinnamyl alcohol, 113.2 g (819.81 mmol) diethyl phosphite, and 1 L of 1,4-dioxane were added to a reaction vessel. After the addition was complete, the mixture was heated to 100 °C with stirring and reacted for 3 h. The system was then cooled to below 20 °C, and 32.8 g (819.81 mmol) of 60% sodium hydride and 180.7 g (670.75 mmol) of 4-[2-(N,N-dimethylamino)ethoxy]benzophenone were added. After the addition was complete, the mixture was stirred at 20-30 °C for 5 h. 1,4-dioxane was removed by vacuum distillation. 500 mL of purified water was added to the residue, and the mixture was stirred at room temperature for 30 min. After filtration, 900 mL of ethanol and 300 mL of purified water were added to the filter cake. The mixture was heated to dissolve the residue, and then slowly cooled to 10-20℃. After filtration and drying of the filter cake, 218.3 g of (Z)-triarylbutenol was obtained, with a yield of 84%.

[0041] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. A method for preparing a toremifene citrate intermediate, characterized in that, Includes the following steps: Cinnamyl alcohol and diethyl phosphite undergo a first reaction in an organic solvent to obtain a first reactant. The obtained first reactant undergoes a second reaction with a base and 4-[2-(N,N-dimethylamino)ethoxy]benzophenone. After the second reaction is completed, the obtained second reactant is distilled under reduced pressure to remove the organic solvent. Water is added to the residue and stirred. The residue is then filtered for a first time to obtain a first filter cake. Water and ethanol are added to the obtained first filter cake, and after dissolution and cooling, the residue is filtered for a second time to obtain a second filter cake. The obtained second filter cake is toremifene citrate intermediate I. The temperature of the first reaction is 60-100℃; The alkali is potassium tert-butoxide; The temperature of the second reaction is 20-30℃; I。 2. The preparation method according to claim 1, characterized in that, The molar ratio of cinnamyl alcohol to diethyl phosphite is 1:0.9-1.

3.

3. The preparation method according to claim 1, characterized in that, The organic solvent is 1,4-dioxane and / or tetrahydrofuran.

4. The preparation method according to claim 1, characterized in that, The mass-to-volume ratio of cinnamyl alcohol to organic solvent is 90-110 g / L.

5. The preparation method according to claim 1, characterized in that, The first reactant is reacted directly with a base and 4-[2-(N,N-dimethylamino)ethoxy]benzophenone in a second reaction without separation or purification.

6. The preparation method according to claim 1, characterized in that, The molar ratio of cinnamyl alcohol to alkali and 4-[2-(N,N-dimethylamino)ethoxy]benzophenone is 1:0.9-1.3:0.7-1.1.

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