A method for preparing fornetupitant

Abstract

The present application discloses a method for preparing fornetupitant, comprising the following steps: stirring netupitant, dialkyl chloromethyl phosphate, an iodide salt, and a ketone solvent; filtering the obtained mixture, concentrating the filtrate, adding an alkane solvent, crystallizing, and filtering to obtain a transition state mixture; dissolving the obtained transition state mixture in the ketone solvent, alcohol solvent, or dioxane, and then adding an acid solution for reaction. After the reaction is complete, adding the ketone solvent or dioxane solvent, stirring for crystallization, filtering, and drying to obtain a crude fornetupitant. The method can obtain fornetupitant with a purity of more than 99.5% and a single impurity of about 0.1%.

Description

Technical Field

[0001] The present application relates to the field of medicine, and in particular to a method for preparing fornetupitant. Background Art

[0002] Fosnetupitant, chemically named 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropionamido)-4-(o-tolyl)pyridin-2-yl)-1-methyl-1-((phosphoryloxy)methyl}piperazin-1-ium chloride hydrochloride, is a prodrug of fosnetupitant. On April 19, 2018, the U.S. FDA approved Helsinn Hlthcare's Akynzeo (Fosnetupitant / Palonosetron) marketing application. Akynzeo is a combination intravenous injection of the 5-HT3 receptor antagonist Palonosetron and the NK-1 receptor antagonist Fosnetupitant, used to prevent nausea and vomiting in cancer patients undergoing chemotherapy. Palonosetron was approved in 2008. This drug is used to prevent nausea and vomiting in the acute phase (within 24 hours) after the start of cancer chemotherapy. Fosnetupitant is a new drug used to prevent nausea and vomiting in the acute phase and delayed phase (from 25 hours to 120 hours after chemotherapy) after the start of cancer chemotherapy. The effectiveness of Akynzeo is based on two clinical trials involving 1,720 subjects receiving cancer chemotherapy. Clinical trials. Subjects were randomly assigned to receive an injection of Akynzeo or oral palonosetron. The two trials were designed to test whether the study drug could prevent vomiting episodes in the acute, delayed, and overall stages of chemotherapy after the start of cancer chemotherapy. Results from the first trial showed that 98.5%, 90.4%, and 89.6% of Akynzeo-treated subjects did not experience vomiting or nausea requiring rescue medication in the acute, delayed, and overall stages of chemotherapy, respectively. In contrast, 89.7%, 80.1%, and 76.5% of subjects treated with oral palonosetron did not experience vomiting or nausea requiring rescue medication in the acute, delayed, and overall stages of chemotherapy, respectively. The second trial showed similar results. Intravenous infusion showed similar safety and good tolerability to oral capsules, increasing compliance and reducing medication pain in patients with advanced cancer. Its structural formula is as follows:

[0003]

[0004] Currently, only patent CN104053652A reports two methods for synthesizing fornetupitant: one is to use netupitant and di-tert-butyl chloromethyl phosphate, with acetonitrile as solvent, under the action of 1,8-bis(dimethylamino)naphthalene, and heat at 90°C for at least 12h to obtain 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropionamido)-4-(o-tolyl)pyridin-2-yl)-1-methyl-1-((phosphoryloxy)methyl}piperazin-1-ium, which is then reacted with HCl to form chloride hydrochloride to obtain fornetupitant. The disadvantages of this scheme are that it requires long-term high-temperature heating, low yield, and a purification step. The first method is to prepare netupitant and di-tert-butyl chloromethyl phosphate, using acetone as solvent, under the action of sodium iodide, nitrogen protection, heating at 50 ° C for at least 6 hours, concentrating to dryness, reacting with HCl to form chloride hydrochloride, crystallizing in 1,4-dioxane at 5 ° C, filtering, and then beating in acetone to prepare netupitant. The defect of this scheme is that a large amount of netupitant is not completely reacted. Using a single dioxane as a crystallization solvent, due to the freezing point of 1,4-dioxane is about 12 ° C, resulting in the complete solidification of the solution at low temperature, making filtration difficult, and there are few subsequent purification steps. There are many related substances and it is impossible to obtain a high-purity product. Summary of the Invention

[0005] The following is a summary of the subject matter described in detail herein. This summary is not intended to limit the scope of the claims.

[0006] The present application provides a method for preparing fornetupitant. By this method, fornetupitant with a purity of more than 99.5% and a single impurity content of about 0.1% can be obtained. The main improvements include reacting at room temperature, crystallizing in ketone and alkane solvents to prepare a transition state product, adding a ketone or dioxane solvent in the acid deprotection step, crystallizing to obtain a crude product, and finally refining the fornetupitant with a ketone solvent and water to obtain a finished product. The fornetupitant obtained by this method has a low content of related substances, a simple process, strong operability, high yield, low cost, and is conducive to industrialization.

[0007] The technical solution of this application is described in detail below.

[0008] The present application provides a method for preparing fornetupitant, which comprises the following steps:

[0009] (1) Netupitant (SM1), dialkyl chloromethyl phosphate (SM2), iodide salt and ketone solvent are stirred; wherein the molar ratio of netupitant: dialkyl chloromethyl phosphate: iodide is 1:1.5-3.0:1.5-3.0.

[0010] (2) filtering the mixture obtained in step (1), concentrating the filtrate, adding an alkane solvent, crystallizing, and filtering to obtain a transition state mixture;

[0011] (3) dissolving the transition state mixture obtained in step (2) in the ketone solvent, alcohol solvent or dioxane, and then adding the acid solution to react. After the reaction is completed, adding the ketone solvent or dioxane solvent, stirring and crystallizing, filtering, and drying to obtain a crude product of fornetupitant.

[0012] In the present application, the method can be represented by the following reaction formula:

[0013]

[0014] In the present application, the alkyl group R in the dialkyl chloromethyl phosphate is selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, allyl, benzyl or trimethylsilyl.

[0015] In the present application, the reaction generates a transition state, i.e., a mixture of formula (I) and formula (II)

[0016]

[0017] Wherein, R is selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, allyl, benzyl or trimethylsilyl.

[0018] In the present application, in step (1), the mixture may be stirred at 10°C-40°C to form a suspended liquid.

[0019] In the present application, in step (1), the ketone solvent may be selected from any one or more of acetone, methyl ethyl ketone, butanone, cyclopentanone, cyclohexanone and methyl isobutyl ketone.

[0020] In the present application, in step (1), the ratio of the ketone solvent to netupitant can be 8 mL / g-10 mL / g.

[0021] Herein, mL / g refers to the ratio of the volume of the solvent to the mass of the solute. For example, the ratio of the ketone solvent to netupitant can be 8 mL / g-10 mL / g, which means that the volume of the ketone solvent is 8-10 times the mass of netupitant.

[0022] In the present application, in step (2), the alkane solvent may be selected from any one or more of pentane, hexane, cyclohexane and heptane.

[0023] In the present application, in step (2), the volume ratio of the ketone solvent to the alkane solvent may be 1:0.5-10.

[0024] In the present application, in step (2), crystallization may be carried out by stirring at -10°C to 10°C.

[0025] In the present application, in step (3), the ketone solvent may be selected from any one or more of acetone, methyl ethyl ketone, butanone, cyclopentanone, cyclohexanone and methyl isobutyl ketone;

[0026] The alcohol solvent may be selected from any one or more of methanol, ethanol and isopropanol.

[0027] In the present application, in step (3), the acid solution may be selected from any one or more of a hydrochloric acid solution, a methanol solution of HCl, an ethanol solution of HCl, and a dioxane solution of HCl.

[0028] In the present application, in step (3), the reaction can be carried out at 10°C-40°C.

[0029] In the present application, in step (3), the transition state mixture may be dissolved in a ratio of 2 mL / g to 3 mL / g of the ketone solvent or alcohol solvent or dioxane to netupitant;

[0030] After the reaction is completed, the ratio of the added ketone solvent or dioxane solvent to the transition state mixture can be 3 mL / g-4 mL / g.

[0031] In the present application, in step (3), crystallization may be carried out by stirring at -10°C to 10°C.

[0032] In this application, the method further comprises:

[0033] (4) adding the crude product of fornetupitant to a ketone solvent, slowly adding water, stirring until the solution is clear, then adding an excess of the ketone solvent, stirring for crystallization, filtering, washing the filter cake with a ketone solvent and an alkane solvent, and drying to obtain fornetupitant.

[0034] In the present application, in step (4), the ketone solvent may be selected from any one or more of acetone, methyl ethyl ketone, butanone, cyclopentanone, cyclohexanone and methyl isobutyl ketone.

[0035] In the present application, in step (4), the alkane solvent may be selected from any one or more of pentane, hexane, cyclohexane and heptane.

[0036] In the present application, in step (4), the crude fornetupitant may be added to the ketone solvent at a ratio of 2 mL / g to 5 mL / g of the crude fornetupitant;

[0037] The ratio of water to crude fornetupitant can be 1 mL / g to 2 mL / g;

[0038] An excess amount of ketone solvent can be added according to the ratio of the ketone solvent to the crude product of fornetupitant being 17 mL / g-20 mL / g.

[0039] In the present application, crystallization can be performed at -10°C to 10°C.

[0040] In this application, the method comprises:

[0041] (1) Stir netupitant, dialkyl chloromethyl phosphate, iodide salt and ketone solvent;

[0042] (2) filtering the mixture obtained in step (1), concentrating the filtrate, adding an alkane solvent, crystallizing, and filtering to obtain a mixture of Formula I and Formula II;

[0043] (3) dissolving the mixture of formula I and formula II obtained in step (2) in the ketone solvent, alcohol solvent or dioxane, and then adding the acid solution to react. After the reaction is completed, adding the ketone solvent or dioxane solvent, stirring and crystallizing, filtering, and drying to obtain a crude product of fornetupitant;

[0044] (4) adding the crude product of fornetupitant to the ketone solvent, slowly adding water, stirring until clear, then adding an excess of the ketone solvent, stirring for crystallization, filtering, washing the filter cake with the ketone solvent and the alkane solvent, and drying to obtain fornetupitant.

[0045] In the present application, netupitant is added to acetone, and then chloromethyl di-tert-butyl phosphate and sodium iodide are added separately under stirring, the temperature is controlled at about 30°C, stirred for 6h-8h, filtered, concentrated in vacuo at 40°C, n-heptane is added, and crystallization is allowed to stand at 0°C for more than 2h, filtered, and a transition state mixture wet product is obtained. The above wet product is added to acetone, stirred and dissolved, hydrochloric acid is added, stirred at about 40°C for 30min, then acetone is added, stirred at about 0°C for 1h, filtered, and vacuum dried at 50°C for more than 2h to obtain a yellow solid, i.e., fornetupitant crude product. The above fornetupitant crude product is added to a mixed solvent of acetone and purified water, stirred and dissolved at about 20°C, acetone is added, stirred at about 0°C for 1h, filtered, and the filter cake is washed with acetone and n-pentane respectively. The filter cake obtained is vacuum dried at 45°C for more than 2h to obtain a white crystalline powder, i.e., fornetupitant.

[0046] In the present application, netupitant is added to acetone, and di-tert-butyl chloromethyl phosphate and sodium iodide are added separately under stirring. The temperature is controlled at about 30°C, stirred for 6-8 hours, filtered, concentrated in vacuo at 40°C, n-heptane is added, and crystallization is allowed to proceed at 0°C for more than 2 hours. Filtered to obtain a wet product of a transition state mixture. The wet product is added to acetone, stirred to dissolve, and then a 4N HCl dioxane solution is added. The mixture is stirred at about 40°C for 30 minutes, and then acetone is added. The mixture is stirred at about 0°C for 1 hour, filtered, and dried in vacuo at 50°C for more than 2 hours to obtain a yellow solid, i.e., crude netupitant. The crude fornetupitant was added to a mixed solvent of acetone and purified water, stirred at about 20°C until dissolved, then acetone was added, stirred at about 0°C for 1 hour, filtered, and the filter cake was washed with acetone and n-pentane respectively. The filter cake was vacuum dried at 45°C for more than 2 hours to obtain a white crystalline powder, i.e., fornetupitant.

[0047] In the present application, netupitant is added to acetone, and di-tert-butyl chloromethyl phosphate and sodium iodide are added separately under stirring, the temperature is controlled at about 30°C, stirred for 6h-8h, filtered, concentrated in vacuo at 40°C, n-pentane is added, and crystallization is allowed to stand at 0°C for more than 2h, filtered, and a transition state mixture wet product is obtained. The above wet product is added to acetone, stirred and dissolved, hydrochloric acid is added, stirred at about 40°C for 30min, then acetone is added, stirred at about 0°C for 1h, filtered, and vacuum dried at 50°C for more than 2h to obtain a yellow solid, i.e., fornetupitant crude product. The above fornetupitant crude product is added to a mixed solvent of acetone and purified water, stirred and dissolved at about 20°C, acetone is added, stirred at about 0°C for 1h, filtered, and the filter cake is washed with acetone and n-pentane respectively. The filter cake obtained is vacuum dried at 45°C for more than 2h to obtain a white crystalline powder, i.e., fornetupitant.

[0048] The purity of fornetupitant obtained by the preparation method described in the present application is above 99.5%, and the yield is above 68%.

[0049] The technical solution of the present application has simple technical steps, mild process conditions, low cost, high yield and few impurities, and is a suitable industrialization route.

[0050] The beneficial technical effects of the technical solution of this application are as follows:

[0051] (1) The reaction is carried out at room temperature, which saves energy and the yield is more than 10% higher than that reported in the patent. Crystallization using a ketone solvent and an alkane solvent system can obtain a high-purity transition state mixed product, which is beneficial for the next step of impurity control.

[0052] (2) Deprotection can be performed at room temperature, saving energy. By adding ketones or dioxane solvents, the product can be crystallized, which not only increases the yield but also removes impurities.

[0053] (3) During the refining stage, since fornetupitant is easily degraded into netupitant at high temperature, the crude product is dissolved in ketone solvents and water at room temperature, and a large amount of poor solvent ketone solvent is added to crystallize the product. This not only inhibits the degradation of the product but also has the effect of removing impurities. The obtained product is also a white crystalline powder, which is better than the properties reported in the patent (white to yellow powder).

[0054] Other features and advantages of the present application will be described in the following description, and in part will become apparent from the description, or will be understood by practicing the present application. The purposes and other advantages of the present application can be achieved and obtained through the structures particularly pointed out in the description, claims and drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] The accompanying drawings are used to provide a further understanding of the technical solution of the present application and constitute a part of the specification. Together with the embodiments of the present application, they are used to explain the technical solution of the present application and do not constitute a limitation on the technical solution of the present application.

[0056] Figure 1 is the mass spectrum of fornetupitant prepared in Example 1 in positive ion mode;

[0057] Figure 2 is a mass spectrum of transition state I in the positive ion mode during the preparation of fornetupitant in Example 1;

[0058] Figure 3 is a mass spectrum of transition state II in the positive ion mode during the preparation of fornetupitant in Example 1;

[0059] Figure 4 is the IR graph of fornetupitant prepared in Example 1;

[0060] Figure 5 is an HPLC chart of fornetupitant prepared in Example 1;

[0061] Figure 6 is an HPLC chart of fornetupitant prepared in Example 2;

[0062] Figure 7 is an HPLC chart of fornetupitant prepared in Example 3;

[0063] Figure 8 This is the HPLC chart of fornetupitant prepared in Comparative Example 1;

[0064] Figure 9 This is the HPLC profile of sodium iodide reference;

[0065] Figure 10 This is the HPLC profile of the netupitant reference;

[0066] Figure 11 This is the HPLC chart of fornetupitant. DETAILED DESCRIPTION

[0067] To make the purpose, technical solutions and advantages of this application more clear, the embodiments of this application will be described in detail below with reference to the accompanying drawings. It should be noted that, unless there is a conflict, the embodiments and features in the embodiments of this application can be combined with each other in any way.

[0068] Table 1 Main materials and reagents

[0069] name level source Netupitant ＞99％ Chengdu Zhengshanda Biopharmaceutical Technology Co., Ltd. Di-tert-butyl chloromethyl phosphate ＞98％ Jiangsu Aikon Biopharmaceutical R&D Co., Ltd. Sodium iodide AR Shanghai Aladdin Biochemical Technology Co., Ltd. acetone AR Sinopharm Chemical Reagent Co., Ltd. n-heptane AR Sinopharm Chemical Reagent Co., Ltd. Dioxane Industrial grade Anhui Jinbang Pharmaceutical Chemical Co., Ltd. 4N HCl dioxane solution Industrial grade Panjin Yanfeng Technology Co., Ltd. hydrochloric acid AR Sinopharm Chemical Reagent Co., Ltd. Methanol AR Sinopharm Chemical Reagent Co., Ltd. n-pentane AR Sinopharm Chemical Reagent Co., Ltd.

[0070] Example 1

[0071] Netupitant (237.6 g, 0.4 mol) was added to 2 L of acetone, and di-tert-butyl chloromethyl phosphate (158.4 g, 0.6 mol) and sodium iodide (115.2 g, 0.6 mol) were added under stirring. The temperature was controlled at about 30 ° C. and stirred for 6 to 8 hours. The mixture was filtered and concentrated in vacuo at 40 ° C. to a volume of 400 mL. 400 mL of n-heptane was added and allowed to stand at 0 ° C. for more than 2 hours for crystallization. The mixture was filtered to obtain a wet product of the transition state mixture.

[0072] The wet product was added to 475 mL of acetone, stirred to dissolve, and then 119 mL of hydrochloric acid (36% to 38%) was added. The mixture was stirred at about 40° C. for 30 min, and then 712 mL of acetone was added. The mixture was stirred at about 0° C. for 1 h, filtered, and vacuum-dried at 50° C. for more than 2 h to obtain a yellow solid, i.e., 252.2 g of crude fornetupitant. The purity according to HPLC area normalization method was 95.0%, and the yield was 81%.

[0073] The crude fornetupitant was added to a mixed solvent of 504 mL of acetone and 252 mL of purified water, stirred at about 20° C. to dissolve, then 5.0 L of acetone was added, stirred at about 0° C. for 1 h, filtered, and the filter cake was washed with 100 mL of acetone and 100 mL of n-pentane, respectively. The resulting filter cake was vacuum-dried at 45° C. for more than 2 h to obtain a white crystalline powder, i.e., 242.1 g of fornetupitant, with a yield of 96%. The purity by area normalization method using HPLC (instrument model: Agilent 1200, which was used in the following examples) was 99.8%, and the maximum single impurity was 0.06%.

[0074] Example 2

[0075] Netupitant (237.9 g, 0.4 mol) was added to 2 L of acetone, and di-tert-butyl chloromethyl phosphate (158.7 g, 0.6 mol) and sodium iodide (115.3 g, 0.6 mol) were added under stirring. The temperature was controlled at about 30 ° C. and stirred for 6 to 8 hours. The mixture was filtered and concentrated in vacuo at 40 ° C. to a volume of 400 mL. 400 mL of n-heptane was added and the mixture was allowed to stand at 0 ° C. for more than 2 hours for crystallization. The mixture was filtered to obtain a wet product of the transition state mixture.

[0076] The wet product was added to 475 mL of acetone, stirred to dissolve, and then 119 mL of 4N HCl in dioxane was added. The mixture was stirred at about 40°C for 30 min, and then 712 mL of acetone was added. The mixture was stirred at about 0°C for 1 h, filtered, and vacuum-dried at 50°C for more than 2 h to obtain a yellow solid, i.e., 275.4 g of crude fornetupitant. The purity according to HPLC area normalization method was 91.4%, and the yield was 88%.

[0077] The crude fornetupitant was added to a mixed solvent of 550 mL of acetone and 275 mL of purified water, stirred at about 20° C. to dissolve, then 5.5 L of acetone was added, stirred at about 0° C. for 1 h, filtered, and the filter cake was washed with 100 mL of acetone and 100 mL of n-pentane, respectively. The filter cake was vacuum-dried at 45° C. for more than 2 h to obtain a white crystalline powder, i.e., 239.6 g of fornetupitant, with a yield of 87%, a purity of 99.5% by HPLC area normalization method, and a maximum single impurity of 0.12%.

[0078] Example 3

[0079] Netupitant (237.6 g, 0.4 mol) was added to 2 L of acetone, and di-tert-butyl chloromethyl phosphate (158.8 g, 0.6 mol) and sodium iodide (115.1 g, 0.6 mol) were added under stirring. The temperature was controlled at about 30 ° C. and stirred for 6 to 8 hours. The mixture was filtered and concentrated in vacuo at 40 ° C. to a volume of 400 mL. 400 mL of n-pentane was added and the mixture was allowed to stand at 0 ° C. for more than 2 hours for crystallization. The mixture was filtered to obtain a wet product of the transition state mixture.

[0080] The wet product was added to 475 mL of acetone, stirred to dissolve, and then 119 mL of hydrochloric acid (36% to 38%) was added. The mixture was stirred at about 40° C. for 30 min, and then 712 mL of acetone was added. The mixture was stirred at about 0° C. for 1 h, filtered, and vacuum-dried at 50° C. for more than 2 h to obtain a yellow solid, i.e., 223.4 g of crude fornetupitant. The purity according to HPLC area normalization method was 97.9%, and the yield was 71%.

[0081] The crude fornetupitant was added to a mixed solvent of 446 mL of acetone and 223 mL of purified water, stirred at about 20° C. to dissolve, then 4.5 L of acetone was added, stirred at about 0° C. for 1 h, filtered, and the filter cake was washed with 100 mL of acetone and 100 mL of n-pentane, respectively. The filter cake was vacuum-dried at 45° C. for more than 2 h to obtain 216.7 g of a white crystalline powder, i.e., fornetupitant. The purity by HPLC area normalization method was 99.8%, the maximum single impurity was 0.09%, and the yield was 97%.

[0082] Comparative Example 1

[0083] Netupitant (33.0 g, 57.0 mmol) was added to 280 mL of acetone, and di-tert-butyl chloromethyl phosphate (22.1 g, 85.4 mmol) and sodium iodide (15.5 g, 103.4 mmol) were added separately with stirring. The temperature was controlled at about 50°C, stirred for 12 h, filtered, and concentrated in vacuo at 40°C to dryness to obtain an oil with a purity of 66.4% by HPLC area normalization method.

[0084] Add 54 mL of methanol and 42 mL of dioxane to a concentration bottle. After dissolving, add 12.6 g of 4N HCl in dioxane. Then, concentrate under vacuum at 40°C. Stir the resulting solution at 5°C for 4 h. After the solution solidifies, crush it, and filter it to obtain a yellow filter cake with a purity of 85.7% by HPLC area normalization method.

[0085] The filter cake was added to 304 mL of acetone, beaten, filtered, washed with 60 mL of acetone, and then washed with n-pentane (114 mL×2). The filter cake was vacuum dried at 60° C. to constant weight to obtain a light yellow solid, i.e., 22.4 g of fornetupitant, with a yield of 51.6%, a purity of 93.4% by HPLC area normalization method, a netupitant content of 4.4%, a sodium iodide content of 1.3%, and 0.3% of other largest impurities.

[0086] Example 4

[0087] Structural confirmation (using the sample prepared in Example 1)

[0088] (1) Infrared absorption spectrum (IR) data (Thermo Nicolet IS 5 infrared spectrometer) Figure 4 ) Test conditions: KBr pellet, resolution: 4cm -1 , Scan times: 64 times, Test range: 400-4000cm -1 .

[0089] Table 2 IR data of fornetupitant prepared in Example 1

[0090] <![CDATA[Absorption peak wave number (cm -1 )]]> Absorption peak intensity Attribution group and vibration type 3388.2 m, broad peak <![CDATA[v -OH ]]> 3000.0 w <![CDATA[v C-H (On-H)]]> 2409.3 w <![CDATA[v C-N (-NH + Cl)]]> 1639.3 s, broad peak <![CDATA[v c＝O (-C=O)]]> 1471.9 m <![CDATA[v c＝C (-C=C-)]]> 1373.6 m <![CDATA[v c-H (-C-H)]]> 1301.2 s, peak <![CDATA[v c-O (-C-O-)]]> 1190.4，1130.6 s <![CDATA[v c-N (-C-N-)]]> 1083.9 m <h2 style=";text-align:left;direction:ltr"><![CDATA[v <h2 style=";text-align:left;direction:ltr"> c-F <h2 style=";text-align:left;direction:ltr"> (-CF3)]]><h2 style=";text-align:left;direction:ltr"> 896.7 m <![CDATA[δ C-H (On-H)]]>

[0091] (2) Nuclear magnetic resonance hydrogen spectrum and phosphorus spectrum ( 1 H-NMR, 31 P-NMR)

[0092] Instrument model: BRUKER AV-400 nuclear magnetic resonance spectrometer. Deuterated methanol was used as solvent.

[0093] 1 H-NMR (CD3OD, 400MHz) δ7.99 (s, 1H), 7.84 (s, 1H), 7.68 (s, 2H), 7.34-7.20 (m, 4H), 7.09 (d, 1H, J=8.0Hz), 5.22 (d, 2H , J = 8.0Hz), 4.21 (m, 2H), 4.01 (m, 2H), 3.80-3.72 (m, 4H), 3.24 (s, 3H), 2.49 (s, 3H), 2.18 (s, 3H), 1.27-1.15 (s, 6H).

[0094] 31 P-NMR (CD3OD, 161MHz) δ2.81 (t, 1P, J=7.9Hz).

[0095] (3) Mass spectrometry (ESI, model: Agilent 1260-6230TOF LC-MS) Figure 1 )

[0096] The molecular weight of fornetupitant is 761.5, of which the molecular weight of the free base is 689.2. The standard is M, and a molecular ion peak (M+1) appears in the mass spectrum. + is 690.2, (M+1) / 2 + The molecular weight of fonetupitant free base is 345.2.

[0097] (4) HPLC purity 99.8%, determined by HPLC area normalization method, i.e., chromatographic column C18 column (4.6 mm × 250 mm, 5 μm); detection wavelength 250 nm; column temperature 25°C; flow rate: 1.0 μl / min, mobile phase A: 0.1% trifluoroacetic acid aqueous solution, mobile phase B: 100% acetonitrile; gradient elution 46 min. Figure 5 )

[0098] Table 3 HPLC elution gradient of fornetupitant prepared in Example 1

[0099]

[0100]

[0101] Fornetupitant is a hydrochloride compound, in which the sodium iodide contained is an inorganic salt, which is difficult to remove using the process of Comparative Example 1 or conventional refining methods; Fornetupitant is a prodrug and is easily degraded into netupitant. The selected refining system must not only inhibit degradation but also remove degraded netupitant, and the refining process of Comparative Example 1 cannot meet this condition. Figure 8 Comparison, in Example 1-Example 3 ( Figure 5-Figure 7 ) The NaI at the retention time (RT) ≈ 2.3 min was reduced to below 0.05%, and the netupitant at RT ≈ 12.5 min was completely refined and removed, and the total amount of impurities was greatly reduced.

[0102] Although the embodiments disclosed in this application are as described above, the contents described are merely embodiments adopted to facilitate understanding of this application and are not intended to limit this application. Any person skilled in the art to which this application belongs may make any modifications and changes in the form and details of the implementation without departing from the spirit and scope disclosed in this application. However, the scope of patent protection of this application shall still be based on the scope defined by the attached claims.

Claims

1. A method for preparing fornetupitant, characterized in that, The method comprises the following steps: (1) stirring netupitant, di-tert-butyl chloromethyl phosphate, iodide salt and acetone at 10° C.-40° C. to react; (2) filtering the mixture obtained in step (1), concentrating the filtrate, adding n-heptane or n-pentane, crystallizing at -10°C to 10°C, and filtering to obtain a transition state mixture; (3) dissolving the transition state mixture obtained in step (2) in acetone or dioxane, then adding an acid solution and reacting at 10° C.-40° C., after the reaction is completed, adding acetone or dioxane solvent, stirring and crystallizing at -10° C.-10° C., filtering, and drying to obtain a crude product of fornetupitant; (4) adding the crude fornetupitant obtained in step (3) to a mixed solvent of acetone and water, stirring until clear, then adding excess acetone, stirring and crystallizing at -10°C to 10°C, filtering, washing the filter cake with acetone and n-pentane, and drying to obtain fornetupitant.

2. The method according to claim 1, wherein In step (1), the ratio of acetone to netupitant is 8 mL / g-10 mL / g.

3. The method according to claim 1, wherein In step (2), the volume ratio of acetone in step (1) to n-heptane or n-pentane in step (2) is 1:0.5-10.

4. The method according to claim 1, wherein In step (3), the acid solution is selected from any one or more of a hydrochloric acid solution and a dioxane solution of HCl.

5. The method according to claim 1, wherein In step (3), dissolving the transition state mixture according to the ratio of acetone or dioxane to netupitant of 2 mL / g to 3 mL / g; After the reaction is completed, the ratio of the added acetone or dioxane solvent to netupitant is 3 mL / g-4 mL / g.

6. The method according to any one of claims 1 to 5, wherein In step (4), the crude fornetupitant is added to a mixed solvent of acetone and water at a ratio of 2 mL / g to 5 mL / g of acetone and a ratio of 1 mL / g to 2 mL / g of water; Excess acetone was added according to the ratio of acetone to crude fornetupitant of 17 mL / g to 20 mL / g.

7. The method according to claim 1, wherein in step (4), the stirring temperature after adding the mixed solvent of acetone and water is 20°C, and the filter cake drying temperature is 45°C.

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