Process for the preparation of the intermediate N-3 of fulvestrant in one pot

Abstract

The application provides a method for preparing fluorvixian intermediate N-3 by one-pot method, which uses fluorvixian intermediate N-5 as raw material, realizes two-step continuous reactions of bromine substitution and A ring aromatization by one-pot method to generate fluorvixian intermediate N-3; the one-pot method specifically comprises the following steps: adding fluorvixian intermediate N-5 dissolved in an organic solvent into a reaction container, adding a bromine reagent after nitrogen replacement, and performing a bromine reaction at normal temperature; after the reaction is completed, a catalyst is directly added, an A ring aromatization reaction occurs at normal temperature; a thiourea aqueous solution and a toluene solvent are added for post-treatment, an organic phase is separated and concentrated to obtain fluorvixian intermediate N-3 crude product, and fluorvixian intermediate N-3 is obtained after separation and purification. The two-step continuous reactions of bromine substitution and A ring aromatization are realized by the one-pot method, the process flow is shortened, the required organic solvent 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 fluorvixian intermediate N-3 are improved.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medical and chemical industry, and particularly relates to a method for preparing fluorofestin intermediate N-3 by one-pot method. BACKGROUND

[0002] Fluorofestin is a drug approved for marketing by the US Food and Drug Administration in 2002 for treating breast cancer. Fluorofestin N-3 is a key intermediate thereof, and its chemical name is (7-alph, 17-bate)-7-(9-bromononyl) estr-1, 3, 5 (10)-triene-3, 17-diol 17-acetate, and its structural formula is as follows:

[0003]

[0004] Patent US20060030552 discloses a synthesis route of fluorofestin N-3 as follows:

[0005]

[0006] In the prior art, N-5 to N-3 is synthesized by two steps of bromination of a side chain segment and A ring aromatization, after the bromination reaction is completed, the generated hydrogen bromide needs to be neutralized by alkali water, and then a large amount of organic solvent is used for extraction, and the mixture of the organic solvent and the reaction solvent makes it difficult to recycle the solvent, resulting in waste of a large amount of organic solvent and generation of waste water; after obtaining N-4, the A ring aromatization is performed, and the post-treatment also needs to use a large amount of water and organic solvent for post-treatment. SUMMARY

[0007] In view of this, the application aims to provide a method for preparing fluorofestin intermediate N-3 by one-pot method, and aims to solve at least one technical problem in the background art.

[0008] The application is implemented in the following manner:

[0009] The method for preparing fluorofestin intermediate N-3 by one-pot method takes fluorofestin intermediate N-5 as raw material, realizes two-step continuous reactions of bromine substitution and A ring aromatization by one-pot method, and generates fluorofestin intermediate N-3;

[0010] The structure of the fluorofestin intermediate N-5 is as shown in the following formula:

[0011]

[0012] In the formula, R is a silicon protection group of a hydroxyl group, and specifically is any one of OTBS, OTMS and OTES;

[0013] The structure of the fluorofestin intermediate N-3 is as shown in the following formula:

[0014]

[0015] The one-pot method specifically comprises:

[0016] The fluorvixlum intermediate N-5 dissolved in an organic solvent is added to a reaction container, nitrogen is replaced after the addition of a bromination reagent, and the bromination reaction is carried out at normal temperature;

[0017] The catalyst is directly added after the bromination reaction is completed, and the A ring aromatization reaction occurs at normal temperature;

[0018] The A ring aromatization reaction product is added to a thiourea aqueous solution and a toluene solvent for post-treatment, the organic phase is separated and concentrated to obtain the crude product of the fulvestrant intermediate N-3, and the fulvestrant intermediate N-3 is obtained after separation and purification.

[0019] Further, 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, the bromination reagent is dibromotriphenylphosphine; the organic solvent is any one of acetonitrile, tetrahydrofuran or dichloromethane, and preferably, the organic solvent is acetonitrile.

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

[0021] Further, the catalyst is lithium bromide and copper bromide.

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

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

[0024] 1. The present application realizes the two-step continuous reaction of bromine substitution and A ring aromatization to generate the fulvestrant intermediate N-3 through the one-pot method, avoids the post-treatment of the bromination reaction, shortens the process flow, effectively reduces the organic solvent required in the reaction process, reduces the amount of wastewater generated in the reaction process, and further improves the yield and purity of the fulvestrant intermediate N-3.

[0025] 2. The present application has simple process and mild reaction, and is suitable for industrialization. BRIEF DESCRIPTION OF DRAWINGS

[0026] Figure 1 The high-performance liquid chromatogram of the product prepared in Example 1 of the present application;

[0027] Figure 2 The nuclear magnetic resonance hydrogen spectrum of the product prepared in Example 1 of the present application;

[0028] Figure 3 The nuclear magnetic resonance carbon spectrum of the product prepared in Example 1 of the present application;

[0029] Figure 4 High resolution mass spectrum of the product prepared for Example 1 of the present application;

[0030] Figure 5 High performance liquid chromatogram of the product prepared for Example 2 of the present application;

[0031] Figure 6 High performance liquid chromatogram of the product prepared for Example 3 of the present application;

[0032] Figure 7 High performance liquid chromatogram of the product prepared for Example 4 of the present application;

[0033] Figure 8 High performance liquid chromatogram of the product prepared for Example 5 of the present application;

[0034] Figure 9 High performance liquid chromatogram of the product prepared for Comparative Example 1 of the present application. DETAILED DESCRIPTION

[0035] In order to make the purpose, technical scheme and advantages of the present application more clear, the present application is further described in detail below in combination with examples. It should be understood that the specific implementation cases described herein are only used to explain the present application, and are not used to limit the present application.

[0036] The present application relates to a method for preparing fluorviesiran intermediate N-3 by one-pot method, which uses fluorviesiran intermediate N-5 as raw material to realize the two-step continuous reaction of bromine substitution and A ring aromatization to generate viesiran intermediate N-3 by one-pot method;

[0037]

[0038] The one-pot method specifically includes:

[0039] The reaction container is added with the fluorviesiran intermediate N-5 dissolved in an organic solvent, nitrogen is replaced after the addition of a bromine reagent, and the bromination reaction is carried out at normal temperature;

[0040] The catalyst is directly added after the bromination reaction is completed, and the A ring aromatization reaction occurs at normal temperature;

[0041] The A ring aromatization reaction product is added with thiourea aqueous solution and toluene solvent for post-treatment, the organic phase is separated and concentrated to obtain viesiran intermediate N-3 crude product, and the viesiran intermediate N-3 is obtained after separation and purification.

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

[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 brominating agent is 1:1.5-1.7. The theoretical molar ratio of fulvestrant intermediate N-5 to the brominating agent is 1:1, and an excess of the brominating agent is used in the present application.

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

[0046] One molecule of hydrogen bromide is generated during the bromination reaction, making the reaction system acidic; during the A ring aromatization reaction, bromine on the copper bromide in the catalyst is then eliminated by lithium bromide to form a double bond, and then interconvert into an aromatic ring. Strong acid hydrogen bromide is generated in 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 fulvestrant intermediate N-3, but reacts with copper salt to generate cuprous bromide precipitate, which is easy to remove; the reaction formula is as follows:

[0047]

[0048] Example 1

[0049] In this example, fulvestrant intermediate N-5 is synthesized into fulvestrant intermediate N-3 by one-pot method, and the reaction formula is as follows:

[0050]

[0051] The specific synthesis steps are as follows: 1 kg of fulvestrant intermediate N-5' (1.745 mol, 1.0 eq.) is dissolved in 5 liters of acetonitrile, and after nitrogen replacement for 3 times, 1.105 kg of dibromotriphenylphosphine (2.618 mol, 1.5 eq.) is added at 20-40°C to generate a bromination reaction, which is completed after 2 hours. Then 0.15 kg of lithium bromide and 0.58 kg of copper bromide are added to the above reaction at 20-40°C to generate an A ring aromatization reaction, which is completed after 3 hours. A mixture solution of 0.3 kg of thiourea and 5 liters of water is directly added to the above reaction liquid, and then 3.5 liters of toluene is added for extraction. After the organic phase is separated, the crude fulvestrant intermediate N-3 is obtained by concentration.

[0052] The crude product of the fulvestrant intermediate N-3 was subjected to silica gel column chromatography (100 mesh silica gel) with a gradient elution of 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 (400 MHz, 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 (100 MHz, 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, fluorovisuge intermediate N-5' is used to one-pot synthesize fluorovisuge intermediate N-3.

[0058] Dissolve 1 kg of fluorovisuge intermediate N-5' (1.745 mol, 1.0 eq.) in 5 liters of acetonitrile, and then add 1.18 kg of dibromotriphenylphosphonium (2.797 mol, 1.6 eq.) after three times of nitrogen replacement at 20-40 °C. Bromination reaction occurs, and the reaction is completed after 2 hours. Then, add 0.15 kg of lithium bromide and 0.58 kg of copper bromide to the above reaction at 20-40 °C, and A ring aromatization reaction occurs. The reaction is completed after 3 hours. Directly add a mixture of 0.3 kg of thiourea and 5 liters of water to the above reaction solution, and then add 3.5 liters of toluene for extraction. After the organic phase is separated, concentrate to obtain crude fluorovisuge intermediate N-3.

[0059] Carry out silica gel column chromatography (100 mesh silica gel) on the crude fluorovisuge intermediate N-3, and elute with a gradient of n-heptane / ethyl acetate = 10 / 1-5 / 1. Collect the eluent containing the product, and then combine and concentrate under reduced pressure until no liquid flows out to obtain 0.73 kg of refined fluorovisuge intermediate N-3 with a HPLC purity of 99.9%. The high performance liquid chromatography (HPLC) spectrum analysis is shown in FIG. 1. Figure 5

[0060] Example 3

[0061] In this example, fluorovisuge intermediate N-5' is used to one-pot synthesize fluorovisuge intermediate N-3.

[0062] Dissolve 1 kg of fluorovisuge intermediate N-5' (1.745 mol, 1.0 eq.) in 5 liters of acetonitrile, and then add 1.18 kg of dibromotriphenylphosphonium (2.797 mol, 1.6 eq.) after three times of nitrogen replacement at 20-40 °C. Bromination reaction occurs, and the reaction is completed after 2 hours. Then, add 0.15 kg of lithium bromide and 0.58 kg of copper bromide to the above reaction at 20-40 °C, and A ring aromatization reaction occurs. The reaction is completed after 3 hours. Directly add a mixture of 0.3 kg of thiourea and 5 liters of water to the above reaction solution, and then add 3.5 liters of toluene for extraction. After the organic phase is separated, concentrate to obtain crude fluorovisuge intermediate N-3.

[0063] Carry out silica gel column chromatography (100 mesh silica gel) on the crude fluorovisuge intermediate N-3, and elute with a gradient of n-heptane / ethyl acetate = 10 / 1-5 / 1. Collect the eluent containing the product, and then combine and concentrate under reduced pressure until no liquid flows out to obtain 0.73 kg of refined fluorovisuge intermediate N-3 with a HPLC purity of 99.9%. The high performance liquid chromatography (HPLC) spectrum analysis is shown in FIG. 1.​Figure 6 as shown.

[0064] Example 4

[0065] This example describes a one-pot synthesis of fulvestrant intermediate N-3 from fulvestrant intermediate N-5".

[0066]

[0067] The specific synthesis procedure is as follows: 1 Kg of fulvestrant intermediate N-5" (1.884 mol, 1.0 eq.) was dissolved in 5 L of acetonitrile, and after three times of nitrogen replacement, 1.19 Kg of dibromotriphenylphosphonium (2.826 mol, 1.5 eq.) was added at 20-40 °C to cause bromination. After 2 hours, the reaction was completed. Then 0.16 Kg of lithium bromide and 0.63 Kg of copper bromide were added to the above reaction at 20-40 °C to cause A ring aromatization. After 3 hours, the reaction was completed. A mixture of 0.33 Kg of thiourea and 5 L of water was directly added to the above reaction solution, followed by the addition of 3.5 L of toluene for extraction. After the organic phase was separated, it was concentrated to obtain crude fulvestrant intermediate N-3. The crude fulvestrant intermediate N-3 was subjected to silica gel column chromatography (100 mesh silica gel), and eluted with n-heptane / ethyl acetate = 10 / 1-5 / 1 gradient to collect the eluent containing the product. The collected eluent was concentrated under reduced pressure until no liquid was discharged, to obtain 0.77 Kg of fine fulvestrant intermediate N-3 with a purity of 99.9% by HPLC. The HPLC chromatogram analysis is shown in Figure 1. Figure 7 as shown.

[0068] Example 5

[0069] This example describes a one-pot synthesis of fulvestrant intermediate N-3 from fulvestrant intermediate N-5".

[0070]

[0071] The specific synthesis steps are as follows: 1 Kg of raloxifene intermediate N-5" (1.745 mol, 1.0 eq) is dissolved in 5 liters of acetonitrile, and after nitrogen replacement for 3 times, 1.105 Kg of dibromotriphenylphosphonium (2.618 mol, 1.5 eq) is added at 20-40 °C to control the bromination reaction, and the reaction is completed after 2 hours. Then 0.15 Kg of lithium bromide and 0.58 Kg of copper bromide are added to the above reaction at 20-40 °C to control the A ring aromatization reaction, and the reaction is completed after 3 hours. A mixture of 0.3 Kg of thiourea and 5 liters of water is directly added to the above reaction solution, and then 3.5 liters of toluene is added for extraction. After the organic phase is separated, it is concentrated to obtain raloxifene intermediate N-3 crude product. The raloxifene intermediate N-3 crude product is subjected to silica gel column chromatography (100 mesh silica gel), and gradient elution is carried out with n-heptane / ethyl acetate = 10 / 1-5 / 1. The eluent containing the product is collected, combined and concentrated under reduced pressure until no liquid flows out. 0.71 Kg of raloxifene intermediate N-3 fine product is obtained, with a HPLC purity of 99.9%. The high performance liquid chromatography (HPLC) spectrum analysis is shown in Figure 1. Figure 8

[0072] Comparative Example 1

[0073] In this comparative example, raloxifene intermediate N-5' is synthesized into raloxifene intermediate N-3 in two steps. The bromination reaction and the A ring aromatization reaction are not continuous, and a purification step of the bromination reaction product is provided. The synthesis process route is as follows:

[0074]

[0075] The specific synthesis method is as follows:

[0076] Bromination reaction: 1 Kg of raloxifene intermediate N-5 is dissolved in 5 liters of acetonitrile, and after nitrogen replacement for 3 times, 1.1 Kg of dibromotriphenylphosphonium is added at 20-40 °C to control the reaction for 2 hours.

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

[0078] A ring aromatization reaction: 0.15 Kg of lithium bromide and 0.58 Kg of copper bromide are added to the above obtained raloxifene intermediate N-4 at 20-40 °C to control the reaction for 3 hours. A mixture of 0.3 Kg of thiourea and 5 liters of water is added to the above reaction solution, and then 3.5 liters of toluene is added for extraction. After the organic phase is separated, it is concentrated to obtain raloxifene intermediate N-3 crude product;

[0079] ​The crude fluorvix intermediate N-3 is subjected to silica gel column chromatography (100 mesh silica gel) with gradient elution of n-heptane / ethyl acetate = 10 / 1 ~ 5 / 1, the eluent containing the product is collected, and the collected eluent is concentrated under reduced pressure to no liquid flow to obtain 0.62 kg of fine fluorvix intermediate N-3 with a purity of 99.4% by HPLC. The HPLC chromatogram of the fine fluorvix intermediate N-3 is shown in Figure 1. Figure 9

[0080] The products of Examples 1 to 3 and Comparative Example 1 are detected to calculate the yield and purity of fluorvix intermediate N-3, wherein the yield is calculated based on the moles of fluorvix intermediate N-5, and the results are shown in Table 1.

[0081] Table 1

[0082]

[0083] Comparative Example 1, the product fluorvix intermediate N-4 after the bromination reaction is subjected to extraction and purification, and then subjected to the subsequent A ring aromatization reaction; while in this example 1, the product of the bromination reaction is not purified and directly subjected to the subsequent A ring aromatization reaction. Based on the fact that both the bromination reaction and the A ring aromatization reaction are carried out in the same organic solvent acetonitrile and in a strong acidic environment, the present example realizes one-pot method for bromination and aromatization, which not only reduces the reaction steps, but also reduces the use of purification reagents by eliminating the need for purification of the product of the bromination reaction, and at the same time, the one-pot method also enables the A ring aromatization reaction and the bromination reaction to share the organic solvent, thereby further reducing the amount of acetonitrile used and indirectly reducing the generation of waste.

[0084] Under the premise of reducing the reaction steps, the yield and purity of the product are improved. As can be seen from the data in Table 1, the yield of fine fluorvix intermediate N-3 in Example 1 is increased by 13.2% and the purity is increased by 0.5% compared with Comparative Example 1.

[0085] The column chromatography method is used to purify the crude fluorvix intermediate N-3 into fine product, which causes loss of product during the column chromatography process, thereby reducing the yield.

[0086] The above examples only express several embodiments of the present application, and the description is more specific and detailed, but it should not be understood as limiting the scope of the present patent. It should be noted that for ordinary skilled persons in the art, without departing from the concept of the present application, a number of modifications and improvements can be made, which are all within the scope of the present application. Therefore, the protection scope of the present patent should be subject to the appended claims.​

Claims

1. A process for the preparation of the fulvestrant intermediate N-3 by one pot method, characterized in that, The method realizes two-step continuous reactions of bromine substitution and A ring aromatization by one-pot method to generate fulvestrant intermediate N-3 from fulvestrant intermediate N-5 as raw material; The structure of the fulvestrant intermediate N-5 is shown in the following formula: ； R is any one of OTBS, OTMS and OTES; The structure of the fulvestrant intermediate N-3 is shown in the following formula: ； The one-pot method specifically comprises: The reaction container is added with the fulvestrant intermediate N-5 dissolved in an organic solvent, and after nitrogen replacement, a bromination reagent is added at 20-40 DEG C to perform bromination reaction at normal temperature; the bromination reagent is dibromotriphenylphosphine, and the organic solvent is acetonitrile; After the bromination reaction is completed, a catalyst is directly added to perform A ring aromatization reaction at normal temperature; The A ring aromatization reaction product is added with a thiourea aqueous solution and a toluene solvent for post-treatment, the organic phase is separated and concentrated to obtain the fulvestrant intermediate N-3 crude product, and the fulvestrant intermediate N-3 is obtained after separation and purification.

2. The process for one pot preparation of fluorvixproie intermediate N-3 as claimed in claim 1 wherein, The molar ratio of the fulvestrant intermediate N-5 to the bromination reagent is 1:1.5-1.

7.

3. The process for one pot preparation of fulvestrant intermediate N-3 as claimed in claim 1 wherein, The catalyst is lithium bromide and copper bromide.

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

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