Preparation method of lurasidone

Abstract

The invention provides a preparation method of lurasidone, and relates to the technical field of organic synthesis. The preparation method comprises the following steps: mixing 4 '-(1, 2-benzisothiazole-3-yl)-(3aR, 7aR)-octahydrospiro [2H-isoindole-2, 1'-piperazine] mesylate (a compound 3), (3aR, 4S, 7R, 7aS)-hexahydro-4, 7-methylenisobenzofuran-1, 3-diketone (a compound 6) and an amination reagent, and synergistically carrying out amination-substitution reaction under a melting condition to obtain lurasidone; the amination reagent comprises ammonium acetate and / or ammonium formate. The lurasidone is prepared by taking a compound 3 and a low-price compound 6 as reaction raw materials and taking ammonium acetate and / or ammonium formate as an amination reagent. The method has the advantages of easily available raw materials, low cost, no need of organic solvents in the reaction process, environmental protection and simple operation.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly relates to a preparation method of lurasidone. Background Art

[0002] Lurasidone, also known as: Lurasidone (Compound 1), English name: Lurasidone, chemical name: (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione. Lurasidone was developed by Sumitomo Pharmaceutical Co., Ltd. of Japan and was first approved by the US Food and Drug Administration (FDA) for marketing on October 28, 2010. In addition, it has been reported that lurasidone can improve cognitive function. Currently, its hydrochloride salt, that is, lurasidone hydrochloride (Compound 2), is generally used clinically. Lurasidone hydrochloride tablets of many companies such as Qilu Pharmaceutical (Hainan) Co., Ltd. in China have been approved for marketing.

[0003]

[0004] Regarding the chemical synthesis of lurasidone, there are mainly two routes:

[0005] Route 1: Prepared by reacting 4'-(1,2-benzisothiazol-3-yl)-(3aR,7aR)-octahydrospiro[2H-isoindole-2,1'-piperazine]methanesulfonate (Compound 3) with (3aR,4S,7R,7aS)-4,7-methano-1H-isoindole-1,3(2H)-dione (Compound 4) in toluene or N,N-dimethylformamide. The process is as follows:

[0006]

[0007] Route 2: Prepared by reacting (1R,2R)-2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]methyl]-cyclohexanemethanamine (Compound 5) with (3aR,4S,7R,7aS)-hexahydro-4,7-methanoisobenzofuran-1,3-dione (Compound 6) in N,N-dimethylformamide. The process is as follows:

[0008]

[0009] For the above-mentioned process routes, in Route 1, the price of Compound 4 is relatively expensive; in Route 2, Compound 5 is not easy to prepare and is generally not sold as an intermediate in industry. In addition, a large amount of organic solvents (such as toluene or N,N-dimethylformamide, etc.) are used in both routes, which not only increases the cost but also inevitably generates a large amount of three wastes during the production process. Summary of the Invention

[0010] In view of this, the object of the present invention is to provide a preparation method of lurasidone. The preparation method provided by the present invention uses easily available raw materials, and no organic solvents are required in the reaction process, which is green and environmentally friendly.

[0011] In order to achieve the above object of the invention, the present invention provides the following technical solutions:

[0012] The present invention provides a preparation method of lurasidone, comprising the following steps:

[0013] Mix 4'-(1,2-benzisothiazol-3-yl)-(3aR,7aR)-octahydrospiro[2H-isoindole-2,1'-piperazine] methanesulfonate, (3aR,4S,7R,7aS)-hexahydro-4,7-methanoisobenzofuran-1,3-dione and an amination reagent, and carry out an amination-substitution reaction under molten conditions to obtain lurasidone; the amination reagent includes ammonium acetate and / or ammonium formate.

[0014] Preferably, the molar ratio of 4'-(1,2-benzisothiazol-3-yl)-(3aR,7aR)-octahydrospiro[2H-isoindole-2,1'-piperazine] methanesulfonate to (3aR,4S,7R,7aS)-hexahydro-4,7-methanoisobenzofuran-1,3-dione is 1:(1.02 - 1.15), and the mass ratio of the amination reagent to 4'-(1,2-benzisothiazol-3-yl)-(3aR,7aR)-octahydrospiro[2H-isoindole-2,1'-piperazine] methanesulfonate is (2 - 3):1.

[0015] Preferably, the temperature of the amination-substitution reaction is 118 - 125 °C, and the time is 4 - 6 h.

[0016] Preferably, after the amination-substitution reaction, the obtained reaction solution is further subjected to post-treatment, and the post-treatment includes:

[0017] Add the reaction solution to an aqueous sodium carbonate solution, and successively carry out stirring, solid-liquid separation and solid-phase water washing to obtain a crude lurasidone product;

[0018] Dry the crude lurasidone product and then carry out recrystallization to obtain a pure lurasidone product; the recrystallization process is subjected to decolorization treatment.

[0019] Preferably, the mass fraction of the aqueous sodium carbonate solution is 5 - 10%; during the addition of the reaction solution, the temperature of the aqueous sodium carbonate solution does not exceed 20 °C.

[0020] Preferably, the reagent used for recrystallization is isopropyl alcohol; the decolorization treatment uses activated carbon.

[0021] Preferably, the recrystallization includes: mixing the dried crude lurasidone with isopropanol, dissolving it under heating conditions to obtain a crude lurasidone solution;

[0022] After mixing the crude lurasidone solution with activated carbon for decolorization treatment, solid-liquid separation is carried out while it is hot to obtain a liquid phase;

[0023] Cool the liquid phase for crystallization.

[0024] Preferably, the heating temperature is 78 - 82 °C; the cooling temperature is 2 - 8 °C.

[0025] Preferably, the time for the decolorization treatment is 0.5 - 1.5 h; the time for the crystallization is 1.5 - 2.5 h.

[0026] Preferably, after the crystallization, it further includes washing and drying the obtained solid in sequence; the reagent used for washing is isopropanol, and the temperature of the isopropanol is 5 °C.

[0027] The present invention provides a preparation method of lurasidone, which includes the following steps: mixing 4'-(1,2-benzisothiazol-3-yl)-(3aR,7aR)-octahydrospiro[2H-isoindole-2,1'-piperazine] methanesulfonate, (3aR,4S,7R,7aS)-hexahydro-4,7-methanoisobenzofuran-1,3-dione and an amination reagent, and carrying out an amination-substitution reaction under melting conditions to obtain lurasidone; the amination reagent includes ammonium acetate and / or ammonium formate. In the present invention, (3aR,4S,7R,7aS)-hexahydro-4,7-methanoisobenzofuran-1,3-dione (compound 6), which is significantly lower in price than compound 4 ((3aR,4S,7R,7aS)-4,7-methano-1H-isoindole-1,3(2H)-dione), is used as a reaction raw material together with 4'-(1,2-benzisothiazol-3-yl)-(3aR,7aR)-octahydrospiro[2H-isoindole-2,1'-piperazine] methanesulfonate (compound 3), and ammonium acetate and / or ammonium formate is used as the amination reagent. Under melting conditions, while compound 6 reacts with the amination reagent to generate compound 4, the obtained compound 4 directly undergoes a substitution reaction with compound 3 to form lurasidone, thereby reducing the residence time of compound 4 in the high-temperature system during the reaction process, that is, an amination-substitution reaction in which amination and substitution are carried out synergistically, resulting in fewer reaction impurities. In the present invention, the raw materials are easily available, the cost is low, no organic solvents are required during the reaction process, it is green and environmentally friendly, and the operation is simple. In addition, due to the amination and substitution reactions being a synergistic process, the reaction selectivity is good, fewer impurities are generated during the process, the yield is higher than that of the conventional process, and the obtained product has a high purity.

[0028] The results of the examples show that when the method provided by the present invention is used to prepare lurasidone, the yield is more than 90.0%, and the product purity is more than 99.48%. Description of the Drawings

[0029] Figure 1 1H-NMR spectrum of the compound lurasidone prepared in Example 1;

[0030] Figure 2 is Figure 1 partial enlarged view of;

[0031] Figure 3 LC-MS mass spectrum of the compound lurasidone prepared in Example 1;

[0032] Figure 4 IR spectrum of the compound lurasidone prepared in Example 1. Detailed Description of the Invention

[0033] The present invention provides a method for preparing lurasidone, comprising the following steps:

[0034] Mix 4'-(1,2-benzisothiazol-3-yl)-(3aR,7aR)-octahydrospiro[2H-isoindole-2,1'-piperazine] methanesulfonate (Compound 3), (3aR,4S,7R,7aS)-hexahydro-4,7-methanoisobenzofuran-1,3-dione (Compound 6) and an amination reagent, and carry out an amination-substitution reaction under molten conditions to obtain lurasidone (Compound 1); the amination reagent includes ammonium acetate and / or ammonium formate.

[0035] In the present invention, unless otherwise specified, the raw materials involved are well-known commercially available products in the art.

[0036] In the present invention, the molar ratio of 4'-(1,2-benzisothiazol-3-yl)-(3aR,7aR)-octahydrospiro[2H-isoindole-2,1'-piperazine] methanesulfonate to (3aR,4S,7R,7aS)-hexahydro-4,7-methanoisobenzofuran-1,3-dione is preferably 1:(1.02 - 1.15), and can be 1:1.05 or 1:1.1; the mass ratio of the amination reagent to 4'-(1,2-benzisothiazol-3-yl)-(3aR,7aR)-octahydrospiro[2H-isoindole-2,1'-piperazine] methanesulfonate is preferably (2 - 3):1, and can be 2.3:1, 2.4:1, 2.5:1 or 2.6:1. In the present invention, the amination reagent also serves as the reaction medium.

[0037] In the present invention, the temperature of the amination-substitution reaction is preferably 118 to 125 °C, and can be 120 or 125 °C. The time is preferably 4 to 6 h, and can be 4, 5 or 6 h.

[0038] In the present invention, the specific operation of the amination-substitution reaction is preferably as follows: First, heat the amination reagent to melt it, and then add 4'-(1,2-benzisothiazol-3-yl)-(3aR,7aR)-octahydrospiro[2H-isoindole-2,1'-piperazine] methanesulfonate (Compound 3) and (3aR,4S,7R,7aS)-hexahydro-4,7-methanoisobenzofuran-1,3-dione (Compound 6) (Compound 3 and Compound 6 will dissolve into the molten amination reagent) to the molten amination reagent, and carry out the amination-substitution reaction.

[0039] Taking the amination reagent as ammonium acetate (NH4Ac) as an example, the reaction formula of the amination-substitution reaction is as follows:

[0040]

[0041] After the amination-substitution reaction, the present invention preferably further includes post-treating the obtained reaction solution. The post-treatment preferably includes:

[0042] Adding the reaction solution to an aqueous sodium carbonate solution, and successively carrying out stirring, solid-liquid separation and solid-phase water washing to obtain a crude product of lurasidone;

[0043] Drying the crude product of lurasidone and then carrying out recrystallization to obtain a pure product of lurasidone; the process of recrystallization undergoes decolorization treatment.

[0044] In the present invention, the mass fraction of the aqueous sodium carbonate solution is preferably 5 to 10%, and can be 7%. In the examples of the present invention, the aqueous sodium carbonate solution is prepared by adding sodium carbonate to water and stirring to dissolve it; the temperature of the aqueous sodium carbonate solution is preferably 10 °C. In the present invention, the mass ratio of the reaction solution to the aqueous sodium carbonate solution is preferably 1:(1.2 to 2), and can be 1:1.3, 1:1.4, 1:1.5 or 1:2; the addition method of the reaction solution is preferably dropwise addition. During the addition of the reaction solution, the temperature of the aqueous sodium carbonate solution is preferably not more than 20 °C. In the present invention, the stirring time is preferably 1 h, and the stirring time is calculated starting from the completion of the addition of the reaction solution. In the present invention, the solid-liquid separation method can be filtration; the solid-phase water washing method is preferably rinsing. In the present invention, the aqueous sodium carbonate solution is an alkaline solution, and through alkalization, the lurasidone mesylate generated in the reaction is freed into lurasidone.

[0045] In the present invention, the drying method may be drying by baking. In the present invention, the reagent used for recrystallization is preferably isopropanol; the decolorization treatment preferably uses activated carbon; the recrystallization method preferably includes:

[0046] Mix the dried lurasidone crude product with isopropanol, and dissolve it under heating conditions to obtain a lurasidone crude product solution;

[0047] After mixing the lurasidone crude product solution with activated carbon for decolorization treatment, perform solid-liquid separation while it is hot to obtain a liquid phase;

[0048] Cool the liquid phase for crystallization.

[0049] In the present invention, the mass of the isopropanol is preferably 3.5 to 4.5 times the theoretical mass of lurasidone; the heating temperature is preferably 78 to 82 °C, and can be 80 °C. In the present invention, isopropanol is preferably added to the dried lurasidone crude product, and the temperature is raised to 78 to 82 °C to dissolve the lurasidone crude product to obtain a lurasidone crude product solution.

[0050] In the present invention, the mass of the activated carbon is preferably 0.025 to 0.03 times the theoretical mass of lurasidone; the decolorization treatment time is preferably 0.5 to 1.5 h, and can be 1 h. Specifically, after adding activated carbon to the lurasidone crude product solution, keep it warm at 78 to 82 °C for 0.5 to 1.5 h. In the present invention, the method of performing solid-liquid separation while it is hot can be hot filtration to obtain a liquid phase (i.e., filtrate).

[0051] In the present invention, the cooling temperature is preferably 2 to 8 °C, and can be 5 °C. The crystallization time is preferably 1.5 to 2.5 h, and can be 2 h. The crystallization is to keep it warm at 2 to 8 °C for 1.5 to 2.5 h.

[0052] In the present invention, after crystallization, it further preferably includes washing and drying the obtained solid in sequence. In the present invention, the solid can be obtained by filtration after crystallization; the reagent used for washing is preferably isopropanol, and the temperature of the isopropanol is preferably 5 °C. In the present invention, the drying method may be drying by baking.

[0053] The preparation method provided by the present invention has easily available raw materials, low cost, convenient operation, and is environmentally friendly; and has a high yield and high product purity.

[0054] To further illustrate the present invention, the following describes in detail the preparation method of lurasidone provided by the present invention with reference to examples, but they should not be construed as limiting the protection scope of the present invention.

[0055] Example 1

[0056] The preparation of lurasidone is as follows:

[0057] In a reaction flask, 1000 g of ammonium acetate was added, and the temperature was raised to 120 °C until the ammonium acetate melted. Then, 423 g (1.0 mol) of Compound 3 (4'-(1,2-benzisothiazol-3-yl)-(3aR,7aR)-octahydrospiro[2H-isoindole-2,1'-piperazine] methanesulfonate) and 174.3 g (1.05 mol) of Compound 6 ((3aR,4S,7R,7aS)-hexahydro-4,7-methanoisobenzofuran-1,3-dione) were slowly added. The mixture was kept at a constant temperature for 5 h until the reaction was completed (monitored by HPLC until the content of Compound 3 was less than 0.3%), and then the reaction was stopped.

[0058] In another reaction flask, 150 g of sodium carbonate was added to 2000 g of water and stirred until dissolved to obtain an aqueous sodium carbonate solution. The solution was cooled to 10 °C, and then the reaction solution obtained above was slowly added to the aqueous sodium carbonate solution. During the addition, the temperature was not allowed to exceed 20 °C. After the addition, the mixture was stirred for 1 h, filtered, and the obtained solid was washed with 1000 g of water to obtain crude lurasidone.

[0059] After drying the obtained crude lurasidone, 2000 g of isopropyl alcohol was added, and the temperature was raised to 80 °C to dissolve the system. Then, 13 g of activated carbon was added, and the mixture was kept at a constant temperature for 1 h. It was filtered while hot, and the filtrate was cooled to 5 °C and kept at a constant temperature for 2 h. After filtration, the obtained solid was washed with 200 g of isopropyl alcohol at 5 °C and then dried to obtain 449.2 g of a white solid, namely lurasidone. Based on Compound 3, the yield was 91.3%. HPLC purity: 99.58%, melting point: 147.7 - 147.9 °C.

[0060] The lurasidone (C 28 H 36 N4O2S) prepared in Example 1 was subjected to nuclear magnetic resonance detection, liquid chromatography - mass spectrometry (LC - MS) detection, and infrared detection, and the spectra were obtained as Figures 1 to 4 shown, where:

[0061] Figure 1 is the 1H - NMR spectrum of lurasidone, Figure 2 is a partially enlarged view of the 1H - NMR spectrum of lurasidone, and the 1H - NMR data are as follows:( 11H-NMR)(DMSO-d6), 600 MHz): δ 1.04~1.06 (m, 3H), 1.14~1.25 (m, 3H), 1.35 (m, 2H), 1.44 (m, 1H), 1.52 (m, 2H), 1.62 (m, 4H), 1.89~1.91 (m, 1H), 2.19~2.23 (m, 1H), 2.56~2.61 (m, 10H), 2.71 (s, 2H), 3.23~3.28 (m, 1H), 3.38 (m, 1H), 3.76~3.80 (m, 1H), 7.47~7.50 (m, 1H), 7.59~7.62 (m, 1H), 8.08~8.11 (m, 2H);

[0062] Figure 3 The LC-MS mass spectrum of lurasidone, [M + H] in positive ion mode + = 493, [M + Na] + = 515 (i.e., M = 492), which is consistent with the molecular composition of C 28 H 36 N4O2S;

[0063] Figure 4 The infrared spectrum of lurasidone, infrared spectrum data are as follows: (IR, KBr, cm -1 -1): 2915 (ν C-H , benzene ring), 2841 (ν CH2 , alicyclic ring), 1770 (ν C＝O ), 1696 (ν C＝O ), 1487 (ν C＝C ), 1423 (γ CH2 ), 1359 (ν C-H ), 1189 (δ N-S ), 1142 (δ C-N ), 1069 (ν C-C ), 820 (γ C-H , substituted benzene), 775 (γ C-H , substituted benzene), 744 (γ C-H , substituted benzene), 715 (ν C-S ).

[0064] Elemental analysis of the compound lurasidone (C 28 H 36 N4O2S, %)(found / calculated): C 68.29 / 68.26, H 7.40 / 7.37, N 11.22 / 11.37.

[0065] Example 2

[0066] The preparation of lurasidone is as follows:

[0067] In a reaction flask, 1000 g of ammonium formate was added, and the temperature was raised to 120 °C until the ammonium formate melted. Then, 423 g (1.0 mol) of Compound 3 and 174.3 g (1.05 mol) of Compound 6 were slowly added. The mixture was kept at a certain temperature for 5 h until the reaction ended (traced by HPLC until the content of Compound 3 was less than 0.3%), and then the reaction was stopped.

[0068] The post-treatment after the reaction was the same as that in Example 1, and 442.6 g of lurasidone was obtained. Based on Compound 3, the yield was 90.0%. HPLC purity: 99.48%.

[0069] Example 3

[0070] The reaction temperature in Example 1 was changed to 125 °C, and the rest was the same as in Example 1. 443.8 g of lurasidone was obtained. Based on Compound 3, the yield was 90.2%. HPLC purity: 99.51%.

[0071] Example 4

[0072] The amount of ammonium acetate fed in Example 1 was increased to 1100 g, and the rest was the same as in Example 1. 448.8 g of lurasidone was obtained. Based on Compound 3, the yield was 91.2%. HPLC purity: 99.56%.

[0073] Example 5

[0074] The amount of Compound 6 fed in Example 1 was changed to 182.6 g (1.1 mol), and the rest was the same as in Example 1. 447.9 g of lurasidone was obtained. Based on Compound 3, the yield was 91.0%. HPLC purity: 99.52%.

[0075] The above are only the preferred embodiments of the present invention and do not impose any formal restrictions on the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A method for preparing lurasidone, characterized in that: The following steps are involved: 4'-(1,2-Benzisothiazol-3-yl)-(3aR,7aR)-octahydrospiro[2H-isoindole-2,1'-piperazine] methanesulfonate, (3aR,4S,7R,7aS)-hexahydro-4,7-methyleneisobenzofuran-1,3-dione and an aminating agent are mixed and subjected to an amination-substitution reaction under melting conditions to obtain lurasidone; the aminating agent includes ammonium acetate and / or ammonium formate.

2. The preparation method according to claim 1, characterized in that: The molar ratio of the 4'-(1,2-benzisothiazol-3-yl)-(3aR,7aR)-octahydrospiro[2H-isoindole-2,1'-piperazine] methanesulfonate to (3aR,4S,7R,7aS)-hexahydro-4,7-methyleneisobenzofuran-1,3-dione is 1:(1.02-1.15), and the mass ratio of the amination reagent to the 4'-(1,2-benzisothiazol-3-yl)-(3aR,7aR)-octahydrospiro[2H-isoindole-2,1'-piperazine] methanesulfonate is (2-3):

1.

3. The preparation method according to claim 1, characterized in that: The temperature of the amination-substitution reaction is 118-125° C. and the time is 4-6 hours.

4. The preparation method according to claim 1, characterized in that: After the amination-substitution reaction, the obtained reaction solution is subjected to post-treatment, and the post-treatment includes: adding the reaction solution into a sodium carbonate aqueous solution, stirring, solid-liquid separation and solid-phase water washing are performed in sequence to obtain a crude lurasidone product; The crude lurasidone is dried and then recrystallized to obtain pure lurasidone; the recrystallization process is decolorized.

5. The preparation method according to claim 4, characterized in that: The mass fraction of the sodium carbonate aqueous solution is 5-10%; during the addition of the reaction solution, the temperature of the sodium carbonate aqueous solution does not exceed 20°C.

6. The preparation method according to claim 4, characterized in that: The reagent used in the recrystallization is isopropanol; and the activated carbon is used in the decolorization treatment.

7. The preparation method according to claim 4 or 6, characterized in that: The recrystallization comprises: mixing the dried crude lurasidone with isopropanol, and dissolving the mixture under heating conditions to obtain a crude lurasidone solution; The crude lurasidone solution is mixed with activated carbon for decolorization, and then solid-liquid separation is performed while hot to obtain a liquid phase; The liquid phase is cooled to effect crystallization.

8. The preparation method according to claim 7, characterized in that: The heating temperature is 78-82°C; the cooling temperature is 2-8°C.

9. The preparation method according to claim 7, characterized in that: The decolorization time is 0.5 to 1.5 hours; the crystallization time is 1.5 to 2.5 hours.

10. The preparation method according to claim 7, characterized in that: After the crystallization, the obtained solid is sequentially washed and dried; the washing agent is isopropanol, and the temperature of the isopropanol is 5°C.

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