Paliperidone and preparation method thereof

Abstract

The present invention belongs to the field of biomedicine technology, and specifically relates to a paliperidone and a preparation method thereof, wherein the paliperidone preparation method comprises the following steps: compound 3 reacts with compound 6 to obtain compound 8, compound 8 reacts with hydroxylamine hydrochloride to obtain the hydrochloride of compound 7, and then cyclizes to obtain a crude compound 1, and the crude compound 1 is purified by primary crystallization to obtain a refined product of compound 1. The purity of the refined product of the final product compound 1 obtained by the preparation method of the present invention is greater than 99.9%, and other unknown impurities are ≤0.05%.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine, and in particular relates to paliperidone and a preparation method thereof. Background Art

[0002] Paliperidone (1), chemically named 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, was developed by Janssen and first approved by the U.S. Food and Drug Administration (FDA) in December 2006. It was subsequently marketed in the European Union, Japan, and China under the trade name Invega, in the form of sustained-release tablets. Paliperidone is a central dopamine type II (DA2) antagonist and 5-hydroxytryptamine type II (5HT2A) receptor antagonist. The drug is suitable for the treatment of acute schizophrenia. It can also be used as a monotherapy for schizoaffective disorder and as an adjunct therapy to mood stabilizers and / or antidepressants. Subsequently, Janssen developed a long-acting ester prodrug of paliperidone, namely paliperidone palmitate (2), which is administered once a month or once every three months. Therefore, paliperidone can be used as a pharmaceutical active ingredient or as an intermediate for preparing paliperidone palmitate.

[0003]

[0004] The US invention patents with publication numbers US4804663A and US5158952A report a method for synthesizing paliperidone. As shown in route 1, compound 3 is used as a raw material, reacted with hydroxylamine hydrochloride to obtain compound 4, and then cyclized under alkaline conditions to obtain compound 5, which is then substituted with compound 6 to obtain paliperidone 1. In the paliperidone API prepared by this route, compounds 5 and 6 that are not completely reacted in the last step and remain in the product are the main impurities. In the United States Pharmacopoeia, the residual limits of paliperidone API compounds 5 and 6 are both ≤0.10%. It was found in the study that these two impurities are not easy to remove, especially compound 6. In the crude paliperidone prepared by the optimized process, the residual amount of compound 5 is about 3.0%, and the residual amount of compound 6 is about 1.2%. After a crystallization from a mixed solvent of ethanol and water (such as 70% ethanol), the residual amount of compound 5 in the first refined paliperidone product is about 0.3% (clearance factor 10), and the residual amount of compound 6 is about 0.2% (clearance factor 6). In order to make both of them meet the pharmacopoeia limit requirement of ≤0.10%, the first refined paliperidone product needs to be crystallized twice, which causes a loss of yield, prolongs the production time, and increases the production cost.

[0005] Route 1:

[0006]

[0007] The Chinese invention patent with publication number CN105481856B reports a synthetic route 2, wherein compound 3 reacts with hydroxylamine hydrochloride to generate compound 4, compound 4 reacts with compound 6 to generate compound 7, and compound 7 is cyclized under alkaline conditions to obtain compound 1. The advantage of this route is that the intermediate compound 7 has a greater polarity than paliperidone due to the presence of hydroxyl groups, and the crude paliperidone is crystallized once with 75% ethanol to obtain a product with a single impurity of ≤0.10%, thus avoiding the problem of poor removal of impurity compounds 5 and 6 in route 1.

[0008] Route 2:

[0009]

[0010] The disadvantage of route 2 is that in the process of preparing compound 4 from compound 3, in addition to the main product 4 (Z form), its E-isomer E-4 will inevitably be generated: In order to remove E-4, compound 4 needs to be crystallized and purified once, resulting in a yield of only 65% ​​for compound 4. Another shortcoming of route 2 is that during the preparation of compound 7, due to the presence of two nucleophilic sites, hydroxyl and amino, in compound 4, the following impurities will be generated under alkaline conditions, and the self-cyclization reaction to generate 7-a is particularly prone to occur. In order to obtain a higher purity compound 7, the crude compound 7 is crystallized and purified with isopropanol, resulting in a yield of only 73% for compound 7.

[0011] Summary of the invention

[0012] In view of the deficiencies in the above-mentioned prior art, the present invention provides paliperidone and a preparation method thereof. The purity of the refined product of the final product compound 1 obtained by the present invention is greater than 99.9%, and other unknown impurities are ≤0.05%.

[0013] The specific technical solutions are as follows:

[0014] The first object of the present invention is to provide a method for preparing paliperidone, comprising the following steps:

[0015] Step 1: Add compound 3, compound 6, an acid-binding agent and a solvent, and react compound 3 with compound 6 to obtain compound 8;

[0016] Step 2: Add hydroxylamine hydrochloride and a solvent to compound 8, and react compound 8 with hydroxylamine hydrochloride to obtain the hydrochloride of compound 7;

[0017] Step 3: Add a base and a solvent to the hydrochloride of compound 7, and cyclize the hydrochloride of compound 7 to obtain a crude product of compound 1;

[0018] Step 4: The crude product of compound 1 is purified by primary crystallization to obtain a refined product of compound 1;

[0019]

[0020] In step 1, although compound 3 has only one amino nucleophilic site, impurities 8-a and 8-b are still generated when compound 8 is generated, which is due to the strong leaving property of the F atom at the carbonyl ortho position of compound 3. When ethanol is used as a solvent and an organic base such as triethylamine is used as an acid-binding agent, the prepared compound 8 contains 10-15% of impurity 8-a and 7-12% of impurity 8-b; when an inorganic base such as potassium carbonate is used as an acid-binding agent, the prepared compound 8 contains 8-12% of impurity 8-a and 5-10% of impurity 8-b; in the present invention, when hydrogen phosphate or phosphate is used as an acid-binding agent, the prepared compound 8 contains less than 0.5% of impurity 8-a and less than 0.2% of impurity 8-b.

[0021]

[0022] Furthermore, in step 1, the acid binding agent is selected from one or more of alkali metals, alkaline earth metals and ammonium hydrogen phosphates or phosphates.

[0023] Further, in step 1, the acid binding agent is selected from one or more of dipotassium hydrogen phosphate, disodium hydrogen phosphate, diammonium hydrogen phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, ammonium dihydrogen phosphate, potassium phosphate, sodium phosphate, and ammonium phosphate.

[0024] Furthermore, in step 1, the acid binding agent is selected from one or more of alkali metal and ammonium hydrogen phosphates, such as potassium dihydrogen phosphate, dipotassium hydrogen phosphate, diammonium hydrogen phosphate, disodium hydrogen phosphate, etc.

[0025] Furthermore, in step 1, the solvent is selected from one or more of alcohols, ketones, N,N-dimethylformamide, and dimethyl sulfoxide, and the solvent may contain 0 to 30% water.

[0026] Furthermore, in step 1, the alcohols include methanol, ethanol, isopropanol, etc., and the ketones include acetone, 2-butanone, etc.

[0027] Furthermore, in step 1, the solvent is selected from alcohols, such as methanol, ethanol, isopropanol, etc.

[0028] Furthermore, in step 1, the reaction temperature is 50 to 150°C, preferably 50 to 100°C.

[0029] Furthermore, in step 1, the catalyst sodium iodide or potassium iodide may be added or not.

[0030] Furthermore, in step 1, a catalyst sodium iodide or potassium iodide may be added, and the amount of sodium iodide or potassium iodide added is 0.5 to 1.0 molar equivalent.

[0031] In step 2, in addition to generating compound 7 (Z-7), its E-isomer E-7 is also generated. In the initial stage of the reaction, the ratio of Z-7 to E-7 is about 60:40. The reaction process is shown below. The generated impurity E-7 has good water solubility due to the intermolecular hydrogen bond between the hydroxyl group of oxime and water. The hydroxyl group of the oxime of the product Z-7 forms an intramolecular hydrogen bond with the F atom, which is difficult to dissolve in water and precipitates from water. At the same time, the conversion of oxime and carbonyl is a reversible reaction. As Z-7 precipitates from water, the equilibrium moves to the right, so that the content of product Z-7 in the reaction solution continues to increase, and the content of impurity E-7 continues to decrease. At the end of the reaction, the ratio of Z-7 to E-7 is usually about (90-95): (3-5). After the reaction is completed, the product Z-7 is filtered to obtain the impurity E-7, which usually contains <0.5%.

[0032]

[0033] Furthermore, in step 2, the reaction temperature is 60-100° C., and the amount of hydroxylamine hydrochloride added is 6-8 molar equivalents.

[0034] Further, in step 2, the solvent is selected from one or more of water, methanol, ethanol, and isopropanol.

[0035] Furthermore, in step 2, hydrochloric acid may be added or not.

[0036] Furthermore, in step 2, hydrochloric acid may be added in an amount of 1 to 2 molar equivalents.

[0037] Furthermore, in step 3, the base is selected from one or more inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc.; the amount of the base added is 2 to 3 molar equivalents.

[0038] Further, in step 3, the base is selected from sodium hydroxide and / or potassium hydroxide.

[0039] Furthermore, in step 3, the solvent is selected from alcohols, water, and a mixed solvent of alcohols and water.

[0040] Furthermore, in step 3, the alcohol is such as methanol, ethanol, or isopropanol.

[0041] In step 3, a base is added for cyclization. After the reaction is completed, the crude product of paliperidone 1 can be obtained by filtration. The main impurity contained is compound 7, and the content is usually 0.2-0.5%.

[0042] Furthermore, step 4 is a crystallization refining step, and the solvent used is selected from an alcohol solvent such as a mixed solvent of methanol, ethanol, isopropanol and water.

[0043] Furthermore, in step 4, the solvent is selected from a mixed solvent of ethanol and water, and the water content in the mixed solvent of ethanol and water is 5-50%.

[0044] Furthermore, in step 4, the water content in the mixed solvent of ethanol and water is 15-25%.

[0045] Furthermore, in step 4, the amount of the solvent used is 10 to 15 times the crude quality of paliperidone 1.

[0046] After the first crystallization purification in step 4, the content of impurity compound 7 can be reduced to ≤0.05%, and other unknown impurities can be reduced to ≤0.05%.

[0047] The second object of the present invention is to provide paliperidone prepared by the above-mentioned method for preparing paliperidone.

[0048] Compared with the prior art, the present invention has the following beneficial effects:

[0049] (1) Compound 6 is a major impurity in the United States Pharmacopoeia and is also an impurity that is difficult to remove. The present invention advances the use of compound 6 and increases the interval between compound 6 and the product, which can greatly reduce the risk of residual compound 6 in the product. In the product of the present invention, the residue of compound 6 is usually undetectable.

[0050] (2) In the present invention, in the reaction of preparing compound 8 in step 1, due to the fact that the leaving ability of the fluorine atom at the ortho position of the carbonyl group of compound 3 and the leaving ability of the chlorine atom of compound 6 are not much different, the reaction selectivity is not high when conventional inorganic bases and organic bases are used as acid-binding agents, and a large amount of impurities 8-a and 8-b are generated. Through the screening of bases, it is found that alkali metals, alkaline earth metals, ammonium hydrogen phosphates and phosphates can greatly improve the selectivity of the reaction and reduce the generation of impurities 8-a and 8-b. Under normal circumstances, the impurity 8-a contained in the compound 8 prepared by this method is less than 0.5%, and the impurity 8-b contained is less than 0.2%. Therefore, it is speculated that the improvement of the reaction selectivity is related to the pKa of hydrochloric acid (pKa-8.0), hydrofluoric acid (pKa 3.15), and phosphoric acid (pKa1 2.12, pKa2 7.20, pKa3 12.36). Selecting an acid-binding agent with appropriate acidity and alkalinity can reduce the leaving driving force of the F atom while maintaining the leaving driving force of the Cl atom, ultimately achieving the purpose of improving the reaction selectivity;

[0051] (3) In the present invention, compound 7 (Z-7) is prepared in step 2, and its E-isomer E-7 is also generated. In the present invention, the difference in solubility between Z-7 and E-7 in water is utilized, and E-7 is fully converted to Z-7 by adding excess hydroxylamine hydrochloride, prolonging the reaction time, using water as a solvent, etc. After the reaction is completed, the product Z-7 is obtained by filtration, and the impurity E-7 is usually less than 0.5%, and no further crystallization purification is required. DETAILED DESCRIPTION

[0052] The principles and features of the present invention are described below in conjunction with examples. The examples are only used to explain the present invention and are not used to limit the scope of the present invention.

[0053] In a specific embodiment, the overall reaction scheme of each embodiment is as follows:

[0054]

[0055] Example 1: Synthesis of Compound 8

[0056] In the reaction flask, 30.0 g of compound 3, 29.2 g of compound 6, 35.9 g of potassium dihydrogen phosphate, 9.5 g of potassium iodide, and 180.0 g of methanol were added, and the temperature was raised to 65°C and reacted for 20 hours. After the reaction, 180.0 g of water was added, cooled to room temperature, filtered, and the filter cake was rinsed with 150.0 g of water and dried to obtain 44.6 g of light yellow solid, namely compound 8, with a yield of 90.1%.

[0057] HPLC area normalization method, purity> 99%, containing impurity 8-a 0.33%, impurity 8-b 0.08%.

[0058] ESI-MS (m / z): 432.18 [M+H] + .

[0059] 1 H NMR (400MHz, DMSO-d6) δ7.94-7.84(m,1H),7.47-7.37(m,1H),7.24(t,J=8.4Hz,1H),5.77-5.66(m,1H),4.42(d,J=3.7Hz,1H ),3.93-3.82(m,1H),3.70-3.51(m,3H),3.45-3.34(m,1H),3.04(s,4H),2.94-2.78(m,2H),2.28(s,3H),2.08-1.70(m,8H).

[0060] Example 2: Synthesis of Compound 8

[0061] In the reaction flask, 30.0 g of compound 3, 28.1 g of compound 6, 21.1 g of disodium hydrogen phosphate, 15.4 g of sodium iodide, and 150.0 g of N,N-dimethylformamide were added, and the temperature was raised to 100°C for 6 hours. After the reaction, 200.0 g of water was added, cooled to room temperature, filtered, and the filter cake was rinsed with 180.0 g of water and dried to obtain 41.2 g of light yellow solid, namely compound 8, with a yield of 83.2%.

[0062] HPLC area normalization method, purity> 99%, containing impurity 8-a 0.40%, impurity 8-b 0.19%.

[0063] Example 3: Synthesis of Compound 8

[0064] In the reaction flask, add 30.0g of compound 3, 29.5g of compound 6, 13.2g of ammonium phosphate, 19.0g of potassium iodide, 240.0g of acetone, and 20g of water, heat to 50-60°C, and react for 36h. After the reaction is completed, cool to room temperature, filter, rinse the filter cake with 200g of water, and dry to obtain 39.7g of yellow solid, namely compound 8, with a yield of 80.3%.

[0065] HPLC area normalization method, purity> 99%, containing impurity 8-a 0.43%, impurity 8-b 0.10%.

[0066] Example 4: Synthesis of the hydrochloride salt of compound 7

[0067] In the reaction flask, add 35.0g of compound 8 prepared in Example 1, 45.1g of hydroxylamine hydrochloride, 8.2g of hydrochloric acid, and 280.0g of water, and heat to 90-100°C. The reaction system first dissolves and then solids precipitate. The reaction is continued for 8h. Cool to 0-10°C, filter, rinse the filter cake with 50.0g of cold water, and dry to obtain 36.9g of light yellow solid, i.e., the hydrochloride of compound 7, with a yield of 94.1%.

[0068] HPLC area normalization method, purity> 99%, impurity E-7 content 0.40%.

[0069] ESI-MS (m / z): 447.22 [M+H] + .

[0070] 1H NMR (400MHz, DMSO-d6) δ10.87(s,1H),7.27(t,J=10.4Hz,2H),7.13(t,J=8.4Hz,1H),5.66(d,J=4.5Hz,1H),4.43(d,J=4.7Hz,1H),3.87(dd,J=1 2.7,6.7Hz,1H),3.65(dd,J=16.6,11.4Hz,1H),2.94(s,2H),2.58(s,2H ),2.37(d,J=35.0Hz,3H),2.23(s,3H),2.09-1.66(m,8H),1.49(s,2H).

[0071] Example 5: Synthesis of the hydrochloride salt of compound 7

[0072] In the reaction flask, add 35.0g of compound 8 prepared in Example 3, 33.8g of hydroxylamine hydrochloride, 16.4g of hydrochloric acid, and 245.0g of ethanol, raise the temperature to 60-70°C, react for 24h, the reaction system first dissolves and then solid precipitates. Cool down to -5-5°C, filter, rinse the filter cake with 50.0g of cold ethanol, and dry to obtain 34.8g of light yellow solid, i.e., the hydrochloride of compound 7, with a yield of 88.7%.

[0073] HPLC area normalization method, purity> 99%, impurity E-7 content 0.18%.

[0074] Example 6: Preparation of crude compound 1

[0075] In the reaction flask, add 33.5g of the hydrochloride of compound 7 prepared in Example 4, 7.8g of potassium hydroxide, and 167.5g of ethanol, raise the temperature to 70-80°C, and react for 5h. After the reaction is complete, add 120.0g of water, cool to 20-30°C, and filter. Rinse the filter cake with 120g of water and dry to obtain 27.5g of a yellow solid, i.e., a crude product of compound 1, with a yield of 92.9%.

[0076] HPLC area normalization method, purity> 99%, impurity compound 7 content 0.32%.

[0077] ESI-MS (m / z): 427.20 [M+H] + .

[0078] 1H NMR(400MHz,)δ7.97(dd,J=8.7,5.3Hz,1H),7.64(dd,J=9.1,2.1Hz,1H),7.23(td,J= 9.1,2.1Hz,1H),5.63(d,J=4.5Hz,1H),4.45-4.35(m,1H),3.93-3.79(m,1H),3.64(dd ,J=9.8,4.3Hz,1H),3.19-3.04(m,1H),3.00(d,J=11.4Hz,2H),2.60(dt,J=8.6,3.9H z,2H),2.36(t,J=7.6Hz,2H),2.23(s,3H),2.14(t,J=10.7Hz,2H),2.05-1.66(m,8H).

[0079] Example 7: Preparation of crude compound 1

[0080] In the reaction flask, add 30.0g of the hydrochloride of compound 7 prepared in Example 5, 7.5g of sodium hydroxide, 120.0g of methanol, and 30.0g of water, raise the temperature to 60-70°C, and react for 3h. After the reaction is complete, add 150.0g of water, cool to 10-20°C, and filter. Rinse the filter cake with 120.0g of water to obtain 22.9g of brown solid, i.e., crude compound 1, with a yield of 86.5%.

[0081] According to the HPLC area normalization method, the content of impurity compound 7 was 0.22%.

[0082] Example 8: Preparation of refined product of compound 1

[0083] In the reaction flask, add 25.0g of the crude product of compound 1 prepared in Example 6, 0.75g of activated carbon, and 375.0g of ethanol (water content 15%), and heat to 70-80°C under nitrogen protection. Filter hot, stir the filtrate to precipitate solid, slowly cool to -5-5°C, and filter. Wash the filter cake with 50.0g of cold ethanol with a water content of 15%, and obtain 22.8g of light yellow solid, i.e., the refined product of compound 1, with a yield of 91.2%.

[0084] HPLC area normalization method, purity> 99.9%, no impurities exceeding the reporting limit of 0.05% were detected.

[0085] Example 9: Preparation of refined product of compound 1

[0086] In the reaction flask, add 25.0g of the crude product of compound 1 prepared in Example 7, 1.20g of activated carbon, and 300.0g of ethanol (water content 25%), and heat to 80-85°C under nitrogen protection. Filter hot, stir the filtrate to precipitate solid, slowly cool to -5-5°C, and filter. Wash the filter cake with 40.0g of cold ethanol with a water content of 25%, and obtain 22.0g of light yellow solid, i.e., the refined product of compound 1, with a yield of 88.0%.

[0087] HPLC area normalization method, purity> 99.9%, no impurities exceeding the reporting limit of 0.05% were detected.

[0088] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing paliperidone, characterized in that: The steps include: Step 1: Add compound 3, compound 6, an acid-binding agent and a solvent, and react compound 3 with compound 6 to obtain compound 8; Step 2: Add hydroxylamine hydrochloride and a solvent to compound 8, and react compound 8 with hydroxylamine hydrochloride to obtain the hydrochloride of compound 7; Step 3: Add a base and a solvent to the hydrochloride of compound 7, and cyclize the hydrochloride of compound 7 to obtain a crude product of compound 1; Step 4: The crude product of compound 1 is purified by primary crystallization to obtain a refined product of compound 1; 2. The method for preparing paliperidone according to claim 1, characterized in that: In step 1, the acid binding agent is selected from one or more of alkali metals, alkaline earth metals and ammonium hydrogen phosphates or phosphates.

3. The method for preparing paliperidone according to claim 2, characterized in that: In step 1, the acid binding agent is selected from one or more of dipotassium hydrogen phosphate, disodium hydrogen phosphate, diammonium hydrogen phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, ammonium dihydrogen phosphate, potassium phosphate, sodium phosphate, and ammonium phosphate.

4. The method for preparing paliperidone according to claim 1, characterized in that: In step 1, the solvent is selected from one or more of alcohols, ketones, N,N-dimethylformamide, and dimethyl sulfoxide.

5. The method for preparing paliperidone according to claim 1, characterized in that: In step 1, the reaction temperature is 50-150°C.

6. The method for preparing paliperidone according to claim 1, characterized in that: In step 2, the reaction temperature is 60-100° C., and the amount of hydroxylamine hydrochloride added is 6-8 molar equivalents.

7. The method for preparing paliperidone according to claim 1, characterized in that: In step 2, the solvent is selected from one or more of water, methanol, ethanol, and isopropanol.

8. The method for preparing paliperidone according to claim 1, characterized in that: In step 3, the base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate; and the amount of the base added is 2 to 3 molar equivalents.

9. The method for preparing paliperidone according to claim 1, characterized in that: In step 3, the solvent is selected from alcohols, water, and a mixed solvent of alcohols and water.

10. Paliperidone prepared by the method for preparing paliperidone according to any one of claims 1 to 9.

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