Method for preparing fulvestrant intermediate N-3 by one-pot method

Abstract

The invention provides a method for preparing a fulvestrant intermediate N-3 by a one-pot method, which comprises the following steps: by taking a fulvestrant intermediate N-5 as a raw material, carrying out two-step continuous reaction of bromine substitution and A-ring aromatization by the one-pot method to generate the fulvestrant intermediate N-3; the one-pot method specifically comprises the following steps: adding fulvestrant intermediate N-5 dissolved in an organic solvent into a reaction container, adding a bromination reagent after nitrogen replacement, and carrying out bromination reaction at normal temperature; after the reaction is finished, directly adding a catalyst, and carrying out A-ring aromatization reaction at normal temperature; and adding a thiourea aqueous solution and a toluene solvent for post-treatment, layering and concentrating an organic phase to obtain a vestrant intermediate N-3 crude product, and separating and purifying to obtain the vestrant intermediate N-3. The two-step continuous reaction of bromine substitution and A-ring aromatization is realized through a one-pot method, the process flow is shortened, the organic solvent required in the reaction process is effectively reduced, the amount of wastewater generated in the reaction process is reduced, and in addition, the yield and purity of the vestrant intermediate N-3 are also improved.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemical industry, and particularly relates to a method for preparing a fulvestrant intermediate N-3 by a one-pot process. Background Art

[0002] Fulvestrant is a drug approved by the U.S. Food and Drug Administration for the treatment of breast cancer in 2002. Fulvestrant N-3 is its key intermediate, and its chemical name is (7-alph, 17-bate)-7-(9-bromononyl) estradiol-1,3,5(10)-triene-3,17-diol 17-acetate, and its structural formula is:

[0003]

[0004] Patent US20060030552 discloses a synthetic route of Fulvestrant N-3 as follows:

[0005]

[0006] In the prior art, N-5 to N-3 are synthesized in two steps through bromination of the side chain segment and aromatization of the A ring. After the bromination reaction, the hydrogen bromide produced in the reaction needs to be neutralized with alkaline water, and then extracted with a large amount of organic solvent. The mixture of the organic solvent and the reaction solvent makes it difficult to recycle the solvent, resulting in a large amount of organic solvent waste and wastewater generation. After obtaining N-4, the A ring is aromatized, and the post-treatment also needs to be carried out with a large amount of water and organic solvent. Summary of the invention

[0007] In view of this, the present invention aims to provide a one-pot method for preparing fulvestrant intermediate N-3, aiming to solve at least one technical problem in the background technology.

[0008] The present invention is achieved in that:

[0009] A one-pot method for preparing a fulvestrant intermediate N-3, wherein the method uses a fulvestrant intermediate N-5 as a raw material and performs a two-step continuous reaction of bromine substitution and A ring aromatization to generate a vestrant intermediate N-3 through a one-pot method;

[0010] The structure of the fulvestrant intermediate N-5 is shown below:

[0011]

[0012] Wherein, R is a silicon protecting group of a hydroxyl group, specifically any one of OTBS, OTMS, and OTES;

[0013] The structure of the vestran intermediate N-3 is shown below:

[0014]

[0015] The one-pot method specifically comprises:

[0016] The fulvestrant intermediate N-5 dissolved in an organic solvent is added to a reaction container, and a bromination reagent is added after nitrogen substitution to carry out a bromination reaction at room temperature;

[0017] After the bromination reaction is completed, the catalyst is directly added to cause the A ring aromatization reaction to occur at room temperature;

[0018] A thiourea aqueous solution and a toluene solvent are added to the A ring aromatization reaction product for post-treatment, and the organic phase is concentrated by layer to obtain a crude product of vesstrant intermediate N-3, which is then separated and purified to obtain vesstrant intermediate N-3.

[0019] Furthermore, the bromination reagent is any one of dibromotriphenylphosphine, a combination of bromine and triphenylphosphine, or a combination of carbon tetrabromide and triphenylphosphine; preferably dibromotriphenylphosphine; and the organic solvent is any one of acetonitrile, tetrahydrofuran, or dichloromethane, preferably acetonitrile.

[0020] Furthermore, the molar ratio of the fulvestrant intermediate N-5 to the bromination reagent is 1:1.5 to 1.7.

[0021] Furthermore, the catalyst uses lithium bromide and copper bromide.

[0022] Furthermore, the molar ratio of lithium bromide to copper bromide is 1:1.5-1.7.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] 1. The present invention realizes the two-step continuous reaction of bromine substitution and A ring aromatization to generate Vestran intermediate N-3 by a one-pot method, thereby avoiding the post-treatment of the bromination reaction, shortening the process flow, effectively reducing the organic solvent required in the reaction process, reducing the amount of wastewater generated in the reaction process, and also improving the yield and purity of Vestran intermediate N-3;

[0025] 2. The process of the present invention is simple, the reaction is mild, and it is suitable for industrial promotion. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 This is the HPLC spectrum of the product obtained in Example 1 of the present invention;

[0027] Figure 2 This is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 1 of the present invention;

[0028] Figure 3 The carbon NMR spectrum of the product obtained in Example 1 of the present invention;

[0029] Figure 4 This is a high-resolution mass spectrum of the product obtained in Example 1 of the present invention;

[0030] Figure 5 This is the HPLC spectrum of the product obtained in Example 2 of the present invention;

[0031] Figure 6 This is the HPLC spectrum of the product obtained in Example 3 of the present invention;

[0032] Figure 7 This is the HPLC spectrum of the product obtained in Example 4 of the present invention;

[0033] Figure 8 This is the HPLC spectrum of the product obtained in Example 5 of the present invention;

[0034] Fig. 9 The HPLC spectrum of the product obtained in Comparative Example 1 of the present invention is shown in FIG. DETAILED DESCRIPTION

[0035] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific implementation cases described herein are only used to explain the present invention and are not used to limit the present invention.

[0036] The present invention relates to a method for preparing a fulvestrant intermediate N-3 by a one-pot method, wherein the fulvestrant intermediate N-5 is used as a raw material, and a two-step continuous reaction of bromine substitution and A ring aromatization is performed by a one-pot method to generate the vestrant intermediate N-3;

[0037]

[0038] The one-pot method specifically comprises:

[0039] The fulvestrant intermediate N-5 dissolved in an organic solvent is added to a reaction container, and a bromination reagent is added after nitrogen substitution to carry out a bromination reaction at room temperature;

[0040] After the bromination reaction is completed, the catalyst is directly added to cause the A ring aromatization reaction to occur at room temperature;

[0041] A thiourea aqueous solution and a toluene solvent are added to the A ring aromatization reaction product for post-treatment, and the organic phase is concentrated by layer to obtain a crude product of vesstrant intermediate N-3, which is then separated and purified to obtain vesstrant intermediate N-3.

[0042] In a specific implementation, the bromination reagent is any one of dibromotriphenylphosphine, a combination reagent of bromine and triphenylphosphine, or a combination reagent of carbon tetrabromide and triphenylphosphine; preferably dibromotriphenylphosphine;

[0043] The organic solvent is any one of acetonitrile, tetrahydrofuran or dichloromethane, preferably acetonitrile.

[0044] In a specific implementation, the molar ratio of the fulvestrant intermediate N-5 to the bromination agent is 1:1.5 to 1.7. The theoretical molar ratio of the fulvestrant intermediate N-5 to the bromination agent is 1:1, and an excess of the bromination agent is used in the present invention.

[0045] In a specific implementation, the catalyst uses lithium bromide and copper bromide; the molar ratio of lithium bromide to copper bromide is 1:1.5-1.7.

[0046] During the bromination reaction, a molecule of hydrogen bromide is generated, making the reaction system acidic; during the A ring aromatization reaction, the copper bromide in the catalyst is brominated, and then lithium bromide eliminates a molecule of hydrogen bromide to form a double bond, and then it is converted into an aromatic ring. Strong acid hydrogen bromide is generated in both the bromine substitution reaction and the A ring aromatization reaction, making the reaction system strongly acidic. Under neutral or acidic conditions, thiourea does not react with the vestrant intermediate N-3, but reacts with copper salt to generate cuprous bromide precipitation, which is easy to remove; the reaction formula is as follows:

[0047]

[0048] Example 1

[0049] In this example, the fulvestrant intermediate N-5 was synthesized into the fulvestrant intermediate N-3 in one pot, and the reaction formula is:

[0050]

[0051] The specific synthesis steps are as follows: 1Kg of Fulvestrant intermediate N-5′ (1.745mol, 1.0eq.) is dissolved in 5L of acetonitrile, and after nitrogen replacement for 3 times, 1.105Kg of dibromotriphenylphosphine (2.618mol, 1.5eq.) is added at 20°C to 40°C to cause bromination reaction, and the reaction is completed after 2 hours. Then 0.15Kg of lithium bromide and 0.58Kg of copper bromide are added to the above reaction at 20°C to 40°C to cause A ring aromatization reaction, and the reaction is completed after 3 hours. A mixed solution of 0.3Kg of thiourea and 5L of water is directly added to the above reaction solution, and then 3.5L of toluene is added for extraction. After the organic phase is separated and concentrated, the crude product of Fulvestrant intermediate N-3 is obtained.

[0052] The crude product of the fulvestrant intermediate N-3 was subjected to silica gel column chromatography (100 mesh silica gel) and gradient elution with n-heptane / ethyl acetate = 10 / 1 to 5 / 1. The eluates containing the product were collected, combined and concentrated under reduced pressure until no liquid flowed out, to obtain 0.74 kg of the fulvestrant intermediate N-3 fine product with an HPLC purity of 99.9%. The high performance liquid chromatography (HPLC) spectrum, nuclear magnetic resonance hydrogen spectrum (HNMR), carbon spectrum (CNMR) and high resolution mass spectrum (HRMS) were as follows: Figures 1 to 4 shown.

[0053] 1 H NMR (400MHz, CDCl3)δ H / ppm:7.15-7.13(d,J=8.0Hz,1H),6.64-6.61(dd,J 1 =8.0Hz,J 2 =4.0Hz,1H),6.55(d,J=4.0Hz,1H),4.83(s,1H,OH),4.73-4.68(t,J=10.0Hz,1H),3.42-3.38(t,J=8.0Hz,2H),2.89-2.84(dd,J 1 =16.0Hz,J 2 =4.0Hz,1H),2.73-2.69(d,J=16.0Hz,1H),2.34-2.20(m,3H),2.06(s,3H ),1.88-1.81(m,3H),1.75-1.19(m,21H),1.04-1.03(m,1H),0.83(s,3H).

[0054] 13 C NMR (100MHz,CDCl3)δ C / ppm:171.91,153.76,136.99,131.55,127.06,116.24,113.00,83.18,46.30,43.10,41.79,37.97,37.14,34.66,34.09,33.30,32.86,29.93,29.63,29.45,28.78,28.20,27.57,27.23,25.65,22.85,21.28,12.13.

[0055] HRMS(ESI)m / z calcd for C 29 H 43 BrO3 + (M+H) + :519.2396,521.2375found:519.2469,521.2459.

[0056] Example 2

[0057] In this example, the fulvestrant intermediate N-5′ was synthesized into the fulvestrant intermediate N-3 by a one-pot method, and the specific steps are as follows:

[0058] 1Kg of Fulvestrant intermediate N-5′ (1.745mol, 1.0eq.) was dissolved in 5L of acetonitrile, and after nitrogen replacement for 3 times, 1.18Kg of dibromotriphenylphosphine (2.797mol, 1.6eq.) was added at 20°C to 40°C to cause bromination reaction, and the reaction was completed after 2 hours. Then 0.15Kg of lithium bromide and 0.58Kg of copper bromide were added to the above reaction at 20°C to 40°C to cause A ring aromatization reaction, and the reaction was completed after 3 hours. A mixed solution of 0.3Kg of thiourea and 5L of water was directly added to the above reaction solution, and then 3.5L of toluene was added for extraction. After the organic phase was separated and concentrated, the crude product of Fulvestrant intermediate N-3 was obtained.

[0059] The crude product of Fulvestrant intermediate N-3 was subjected to silica gel column chromatography (100 mesh silica gel) and gradient elution with n-heptane / ethyl acetate = 10 / 1 to 5 / 1. The eluates containing the product were collected, combined and concentrated under reduced pressure until no liquid flowed out, to obtain 0.73 kg of Fulvestrant intermediate N-3 fine product with HPLC purity of 99.9%. Its high performance liquid chromatography (HPLC) spectrum analysis is as follows: Figure 5 shown.

[0060] Example 3

[0061] In this example, the fulvestrant intermediate N-5′ was synthesized into the fulvestrant intermediate N-3 in one pot:

[0062] 1Kg of Fulvestrant intermediate N-5′ (1.745mol, 1.0eq.) was dissolved in 5L of acetonitrile, and after nitrogen replacement for 3 times, 1.25Kg of dibromotriphenylphosphine (2.967mol, 1.7eq.) was added at 20°C to 40°C to cause bromination reaction, and the reaction was completed after 2 hours. Then 0.15Kg of lithium bromide and 0.58Kg of copper bromide were added to the above reaction at 20°C to 40°C to cause A ring aromatization reaction, and the reaction was completed after 3 hours. A mixed solution of 0.3Kg of thiourea and 5L of water was directly added to the above reaction solution, and then 3.5L of toluene was added for extraction. The organic phase was separated and concentrated to obtain the crude product of Fulvestrant intermediate N-3.

[0063] The crude product of Fulvestrant intermediate N-3 was subjected to silica gel column chromatography (100 mesh silica gel) and gradient elution with n-heptane / ethyl acetate = 10 / 1 to 5 / 1. The eluates containing the product were collected, combined and concentrated under reduced pressure until no liquid flowed out to obtain 0.74 kg of the refined product of Fulvestrant intermediate N-3 with HPLC purity of 99.8%. Its high performance liquid chromatography (HPLC) spectrum analysis is as follows: Figure 6 shown.

[0064] Example 4

[0065] In this example, the fulvestrant intermediate N-5″ was synthesized into the fulvestrant intermediate N-3 by a one-pot method, and the reaction formula is:

[0066]

[0067] The specific synthesis steps are as follows: 1 kg of fulvestrant intermediate N-5″ (1.884 mol, 1.0 eq.) was dissolved in 5 liters of acetonitrile, and after nitrogen replacement for 3 times, 1.19 kg of dibromotriphenylphosphine (2.826 mol, 1.5 eq.) was added at 20°C to 40°C to cause bromination reaction, which was completed after 2 hours. Then 0.16 kg of lithium bromide and 0.63 kg of copper bromide were added to the above reaction at 20°C to 40°C to cause A ring aromatization reaction, which was completed after 3 hours. Directly add the above reaction solution to A mixed solution of 0.33 kg of thiourea and 5 liters of water was added, and then 3.5 liters of toluene was added for extraction. The organic phase was separated and concentrated to obtain a crude product of the intermediate N-3 of Fulvestrant. The crude product of the intermediate N-3 of Fulvestrant was subjected to silica gel column chromatography (100 mesh silica gel), and the gradient elution was performed with n-heptane / ethyl acetate = 10 / 1 to 5 / 1. The eluate containing the product was collected, combined and concentrated under reduced pressure until no liquid flowed out, to obtain 0.77 kg of the fine product of the intermediate N-3 of Fulvestrant, with an HPLC purity of 99.9%. The high performance liquid chromatography (HPLC) spectrum analysis thereof is as follows: Figure 7 shown.

[0068] Example 5

[0069] In this example, the fulvestrant intermediate N-5″′ was synthesized into the fulvestrant intermediate N-3 by a one-pot method, and the reaction formula is:

[0070]

[0071] The specific synthesis steps are as follows: 1 kg of fulvestrant intermediate N-5″′ (1.745 mol, 1.0 eq) was dissolved in 5 liters of acetonitrile, and after nitrogen replacement for 3 times, 1.105 kg of dibromotriphenylphosphine (2.618 mol, 1.5 eq) was added at 20°C to 40°C to cause bromination reaction, which was completed after 2 hours. Then 0.15 kg of lithium bromide and 0.58 kg of copper bromide were added to the above reaction at 20°C to 40°C to cause A ring aromatization reaction, which was completed after 3 hours. Directly add the above reaction solution to A mixed solution of 0.3 kg of thiourea and 5 liters of water was added, and then 3.5 liters of toluene was added for extraction. The organic phase was separated and concentrated to obtain a crude product of the intermediate N-3 of Fulvestrant. The crude product of the intermediate N-3 of Fulvestrant was subjected to silica gel column chromatography (100 mesh silica gel), and the gradient elution was performed with n-heptane / ethyl acetate = 10 / 1 to 5 / 1. The eluate containing the product was collected, combined and concentrated under reduced pressure until no liquid flowed out, to obtain 0.71 kg of the fine product of the intermediate N-3 of Fulvestrant, with an HPLC purity of 99.9%. The high performance liquid chromatography (HPLC) spectrum analysis thereof is as follows: Figure 8 shown.

[0072] Comparative Example 1

[0073] In this comparative example, the fulvestrant intermediate N-5′ is synthesized into the fulvestrant intermediate N-3 in two steps, the bromination reaction and the A ring aromatization reaction are carried out discontinuously, and a purification step of the bromination reaction product is provided in the middle; the synthesis process route is:

[0074]

[0075] The specific synthesis method is as follows:

[0076] Bromination reaction: 1 kg of Fulvestrant intermediate N-5 was dissolved in 5 liters of acetonitrile, and after nitrogen replacement for 3 times, 1.1 kg of dibromotriphenylphosphine was added at 20°C to 40°C and the reaction was continued for 2 hours;

[0077] Purification of the bromination reaction product: Add sodium carbonate aqueous solution (0.3 kg sodium carbonate, 8 kg water) to the above reaction solution, and then add 10 L ethyl acetate for extraction. After the organic phase is separated, it is dried over 0.05 kg anhydrous sodium sulfate, filtered and concentrated to obtain Fulvestrant intermediate N-4;

[0078] Aromatization reaction of ring A: The above-obtained Fulvestrant intermediate N-4 was dissolved in 5.5 liters of acetonitrile, and 0.15 kg of lithium bromide and 0.58 kg of copper bromide were added at 20°C to 40°C, and the reaction was carried out for 3 hours. A mixed solution of 0.3 kg of thiourea and 5 liters of water was added to the above reaction solution, and then 3.5 liters of toluene were added for extraction. The organic phase was separated and concentrated to obtain a crude product of Fulvestrant intermediate N-3;

[0079] The crude product of Fulvestrant intermediate N-3 was then subjected to silica gel column chromatography (100 mesh silica gel) and gradient elution with n-heptane / ethyl acetate = 10 / 1 to 5 / 1. The eluates containing the product were collected, combined and concentrated under reduced pressure until no liquid flowed out, to obtain 0.62 kg of Fulvestrant intermediate N-3 fine product with HPLC purity of 99.4%. Its high performance liquid chromatography (HPLC) spectrum analysis is as follows: Fig. 9 shown.

[0080] The products of Examples 1 to 3 and Comparative Example 1 were tested, and the yield and purity of the fulvestrant intermediate N-3 were calculated, wherein the yield was calculated based on the molar amount of the fulvestrant intermediate N-5. The results are shown in Table 1.

[0081] Table 1

[0082]

[0083] Comparative Example 1 Compared with Example 1, after the bromination reaction is completed, the product Fulvestrant intermediate N-4 is extracted and purified, and then the subsequent A ring aromatization reaction is carried out; while the product of the bromination reaction in Example 1 is not purified and the subsequent A ring aromatization reaction is directly carried out. Since the bromination reaction and the A ring aromatization reaction both use the same organic solvent acetonitrile, and both are carried out in a strongly acidic environment, the embodiment of the present invention realizes the bromination and aromatization in a one-pot process, which not only reduces the reaction steps, but also does not need to purify the bromination reaction product, thereby reducing the use of purification reagents. At the same time, the one-pot process also allows the A ring aromatization reaction and the bromination reaction to share an organic solvent, thereby further reducing the amount of acetonitrile used, and indirectly reducing the generation of waste.

[0084] The examples of the present invention have improved product yield and purity under the premise of reducing the number of reaction steps. It can be seen from the data in Table 1 that compared with Comparative Example 1, the yield of the fulvestrant intermediate N-3 fine product in Example 1 is increased by 13.2%, and the purity is increased by 0.5%.

[0085] The present invention adopts a column chromatography method to purify the crude product of the fulvestrant intermediate N-3 into a fine product, and the column chromatography process causes product loss, thereby reducing the yield.

[0086] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A one-pot method for preparing fulvestrant intermediate N-3, characterized in that: The method uses the fulvestrant intermediate N-5 as a raw material, and realizes a two-step continuous reaction of bromine substitution and A ring aromatization to generate the vestrant intermediate N-3 through a one-pot method; The structure of the fulvestrant intermediate N-5 is shown below: Wherein, R is any one of OTBS, OTMS, and OTES; The structure of the vestran intermediate N-3 is shown below: The one-pot method specifically comprises: The fulvestrant intermediate N-5 dissolved in an organic solvent is added to a reaction container, and a bromination reagent is added after nitrogen substitution to carry out a bromination reaction at room temperature; After the bromination reaction is completed, the catalyst is directly added to cause the A ring aromatization reaction to occur at room temperature; A thiourea aqueous solution and a toluene solvent are added to the A ring aromatization reaction product for post-treatment, and the organic phase is concentrated by layer to obtain a crude product of vesstrant intermediate N-3, which is then separated and purified to obtain vesstrant intermediate N-3.

2. The one-pot method for preparing fulvestrant intermediate N-3 according to claim 1, characterized in that: The bromination reagent is any one of dibromotriphenylphosphine, a combination reagent of bromine and triphenylphosphine, or a combination reagent of carbon tetrabromide and triphenylphosphine; and the organic solvent is any one of acetonitrile, tetrahydrofuran, or dichloromethane.

3. The one-pot method for preparing fulvestrant intermediate N-3 according to claim 1 or 2, characterized in that: The molar ratio of the fulvestrant intermediate N-5 to the bromination reagent is 1:1.5 to 1.

7.

4. The one-pot method for preparing fulvestrant intermediate N-3 according to claim 1, characterized in that: The catalyst uses lithium bromide and copper bromide.

5. The one-pot method for preparing fulvestrant intermediate N-3 according to claim 4, characterized in that: The molar ratio of lithium bromide to copper bromide is 1:1.5-1.7.

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