Epiprazole methyl fatty acid ester and preparation method thereof

Abstract

The present invention discloses an epipirazole methyl fatty acid ester and a preparation method thereof. Specifically disclosed is an epipirazole methyl fatty acid ester and a pharmaceutically acceptable salt thereof, which are prepared by the following method: in a solvent, under the action of a base and a catalyst, a compound as shown in formula II reacts with a compound as shown in formula III to obtain an epipirazole methyl fatty acid ester as shown in formula I. The epipirazole methyl fatty acid ester of the present invention can be used as a reference substance for the detection of epipirazole fatty acid esters, which is convenient for controlling the content of related substances in epipirazole fatty acid esters and related preparations. On the other hand, it can also be used as a prodrug of epipirazole, which is metabolized to epipirazole in plasma or whole blood, and has a fast metabolic rate.

Description

Technical Field

[0001] The invention relates to epiprazole methyl fatty acid ester and a preparation method thereof. Background Art

[0002] Brexpiprazole (BPZ), chemically named 7-(4-(4-(benzo[b]thiophen-4-yl)piperazine-1-yl)butanol)quinoline-2(1H)-one, has a chemical structure as shown below.

[0003]

[0004] Ipiriprazole was launched in 2015 and can be used as an adjunctive treatment for schizophrenia and major depressive disorder.

[0005] Methyl (7-(4-(4-(benzo[b]thiophene-4-yl)piperazine-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)laurate, commonly known as epipiprazole laurate, abbreviated as BPZL, has the following structural formula:

[0006]

[0007] As a prodrug of irinotecan, lauric acid ester of irinotecan can be used to treat schizophrenia. The structure is disclosed in patent CN 103781783 A, and this structure is very promising to be developed into a long-acting injection product, but the rate at which irinotecan lauric acid ester is metabolized to irinotecan in plasma or whole blood is relatively slow.

[0008] There are very few reports in patents and numerous literatures on the impurities generated during the synthesis and storage of ipriprazole laurate. However, impurity research is an important part of the drug development process and is directly related to the quality control and safety of the drug. Summary of the invention

[0009] The technical problem to be solved by the present invention is to overcome the lack of research on epiriprazole laurate and other epiriprazole fatty acid ester related substances with similar structures in the prior art, and the defects of epiriprazole laurate in slow metabolism, and provide an epiriprazole methyl fatty acid ester and a preparation method thereof. The preparation method of the present invention is simple, and the obtained epiriprazole methyl fatty acid ester can be used as a reference substance for epiriprazole fatty acid ester detection, which is convenient for controlling the content of related substances in epiriprazole laurate and related preparations, and can also be used as a prodrug of epiriprazole, which is metabolized to epiriprazole in plasma or whole blood, and has a fast metabolism rate.

[0010] The present invention solves the above technical problems through the following technical solutions:

[0011] The present invention provides epiprazole methyl fatty acid ester and pharmaceutically acceptable salts thereof as shown in Formula I:

[0012]

[0013] Here, n is an integer from 4 to 16.

[0014] In one embodiment of the present invention, n is 4, 8, 10, 14 or 16.

[0015] The present invention also provides a method for preparing the epiprazole methyl fatty acid ester as shown in Formula I, which comprises the following steps:

[0016] In a solvent, under the action of a base and a catalyst, the compound represented by formula II reacts with the compound represented by formula III to obtain the epipiprazole methyl fatty acid ester represented by formula I;

[0017]

[0018] Wherein, X is a halogen, and n is defined as described in any one of the present invention.

[0019] In one embodiment of the present invention, X is Cl or Br; for example Cl.

[0020] In a certain embodiment of the present invention, the molar ratio of the compound represented by formula II to the compound represented by formula III is 1:(2-4), for example 1:3.

[0021] In a certain embodiment of the present invention, the solvent may be a commonly used solvent for such reactions in the art. Preferably, the solvent is an ether solvent, preferably tetrahydrofuran and / or dioxane.

[0022] In one embodiment of the present invention, the amount of the solvent used can be the conventional amount used in this type of reaction in the art. Preferably, the volume mass ratio of the solvent to the compound shown in Formula II is (15-25) mL / g, for example 20 mL / g.

[0023] In one embodiment of the present invention, the base may be a base commonly used in this type of reaction in the art. Preferably, the base is one or more of sodium ethoxide, sodium hydrogen hydride, sodium methoxide, sodium tert-butoxide and potassium tert-butoxide.

[0024] In a certain embodiment of the present invention, the amount of the base used can be the conventional amount used in this type of reaction in the art. Preferably, the mass ratio of the base to the compound shown in Formula II is (0.25-0.32):1, for example 0.28:1.

[0025] In one embodiment of the present invention, the catalyst may be a catalyst commonly used in this field for such reactions. Preferably, the catalyst is potassium iodide and / or sodium iodide.

[0026] In one embodiment of the present invention, the amount of the catalyst used can be the conventional amount used in this type of reaction in the art. Preferably, the mass ratio of the catalyst to the compound shown in Formula II is (0.05-0.15):1, for example 0.1:1.

[0027] In one embodiment of the present invention, the reaction temperature may be a common temperature for such reactions in the art, preferably, the reaction temperature is 35-50°C.

[0028] In a certain embodiment of the present invention, the progress of the reaction can be monitored by conventional detection methods in the art (such as TLC, HPLC or GC), and the disappearance of the compound shown in Formula II is generally used as the endpoint of the reaction. Preferably, the reaction time is 1.5-4 hours, for example 2.5 hours.

[0029] In one embodiment of the present invention, the preparation method of the epiprazole methyl fatty acid ester as shown in formula I comprises the following steps: in a solvent, the compound as shown in formula II is first reacted with a base, and then reacted with a compound as shown in formula III under the action of a catalyst.

[0030] In a certain embodiment of the present invention, the preparation method of the epiprazole methyl fatty acid ester as shown in Formula I may further include the following post-treatment steps: quenching the reaction with water (such as ice water), extracting with an organic solvent (such as ethyl acetate), combining the organic phases, concentrating and then performing column chromatography.

[0031] The present invention also provides the use of the epiriprazole methyl fatty acid ester as shown in formula I as a reference substance for related substances in the quality control of epiriprazole fatty acid ester.

[0032] In the present invention, the related substances refer to intermediates and side reaction products that may exist during the preparation and storage of drugs.

[0033] The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention and a relatively nontoxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acid includes an inorganic acid, and the inorganic acid includes, but is not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acid includes organic acids, including but not limited to acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, bitartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthoic acid)), amino acids (e.g., glutamic acid, arginine), etc. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0034] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0035] The reagents and raw materials used in the present invention are commercially available.

[0036] The positive and progressive effects of the present invention are:

[0037] (1) Provides a control substance that can be used as a detection reference substance for epiprazole fatty acid esters, so as to facilitate the control of the content of related substances in epiprazole fatty acid esters and related preparations;

[0038] (2) It can also be used as a prodrug of ipirazole, which is metabolized into ipirazole in plasma or whole blood at a relatively fast rate. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 The blood concentration change curve of compound A3 and epiriprazole laurate metabolism in the whole blood metabolism experiment.

[0040] Figure 2 In the plasma metabolism experiment, the blood concentration change curve of compound A3 and epiriprazole laurate metabolism. DETAILED DESCRIPTION

[0041] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples.

[0042] In the following examples, the purity of the product was determined by HPLC under the following conditions:

[0043] Chromatographic column: octadecylsilane bonded silica gel.

[0044] Mobile phase: 0.15% triethylamine solution (PH 3.50) was used as mobile phase A, and pure acetonitrile solution was used as mobile phase B; the ratio of mobile phase A to mobile phase B was 1:9.

[0045] Mobile phase flow rate: 1.5 ml / min;

[0046] Column temperature: 35°C;

[0047] Detection wavelength: 220nm

[0048] Injection volume: 10 μL.

[0049] Example 1: Preparation of Compound A1 (n=4)

[0050] 10.02 g of epiriprazole was added to 200 mL of dioxane, 2.78 g of NaH was added in batches, the reaction was continued for 30 min, 1.00 g of KI was added, 17.22 g of methyl chloromethoxyhexanoate was measured, slowly added dropwise, and the reaction was continued for 2 h. The reaction was quenched with ice water, extracted with ethyl acetate 3 times, the upper layer solutions were combined and washed twice with saturated brine, and dehydrated with anhydrous magnesium sulfate, rotary evaporated, weighed, mixed (1.5 times), column chromatographed, and the chromatographic solution was rotary evaporated to obtain compound A1, with an HPLC purity of 99.20%.

[0051] Example 2: Preparation of Compound A2 (n=8)

[0052] 10.10 g of epiriprazole was added to 200 mL of tetrahydrofuran, and 2.80 g of C2H5ONa was added in batches, and the mixture was reacted for 30 min. 1.03 g of NaI was added, and 17.20 g of methyl chloromethoxydecanoate was measured and slowly added dropwise, and the mixture was reacted for 2 h. The reaction was quenched with ice water, and the mixture was extracted with ethyl acetate for 3 times. The upper layer solutions were combined and washed twice with saturated brine, and dehydrated with anhydrous magnesium sulfate, and the mixture was rotary evaporated, weighed, mixed (1.5 times), and subjected to column chromatography. The chromatographic solution was rotary evaporated to obtain compound A2, and the HPLC purity was 99.27%.

[0053] Example 3: Preparation of Compound A3 (n=10)

[0054] 10.01 g of epiriprazole was added to 200 mL of tetrahydrofuran, 2.82 g of CH3NaO was added in batches, the reaction was continued for 30 min, 1.01 g of KI was added, 17.23 g of methyl chloromethoxylaurate was measured, and the reaction was continued for 2 h. The reaction was quenched with ice water, extracted with ethyl acetate for 3 times, the upper layer solution was combined and washed twice with saturated brine, and dehydrated with anhydrous magnesium sulfate, rotary evaporated, weighed, mixed (1.5 times), column chromatographed, and the chromatographic solution was rotary evaporated to obtain compound A3, with an HPLC purity of 99.38%. 1 H NMR (400MHz, CDCl3) δ7.62(d,J=9.5Hz,1H),7.56(d,J=8.0Hz,1H),7.49–7.38(m,1H),7.28(t,J=7. 8Hz,1H),6.99(s,1H),6.91(d,J=7.6Hz,1H),6.85(d,J=8.6Hz,1H),6.52(d,J=9.4Hz,1H),5.90(s,1 H),5.44(s,1H),4.12(t,J=6.0Hz,1H),3.25(s,1H),2.81(s,1H),2.65–2.58(m,1H),2.22(t,J=7.6H z,1H),1.98–1.87(m,1H),1.87–1.78(m,1H),1.57–1.48(m,1H),1.27(s,4H),0.90(t,J=6.6Hz,1H).

[0055] 13C NMR(101MHz, CDCl3)δ172.68(s),162.58(s),161.06(s),147.79(s),140.68(s),140.29(s),139.90(s),133 .60(s),129.55(s),124.59(s),121.34(s),117.60(s),116.69(s),114.27(s),111.81(s),110.70(s),99.49 (s),86.50(s),70.41(s),67.66(s),57.64(s),52.96(s),51.34(s),33.73(s),31.47(s),29.26(s),29.15(t ,J=12.3Hz),29.01(s),28.90(s),28.80(s),28.62(s),26.71(s),24.11(s),22.70(s),22.25(s),13.70(s).

[0056] The molecular ion peak of compound A3 detected by MS was m / z 676.38.

[0057] Example 4: Preparation of Compound A3 (n=10)

[0058] 10.02 g of epiriprazole was added to 200 mL of dioxane, heated in a water bath at 55°C and stirred until completely dissolved, the heating was turned off, and when the temperature dropped to 40°C, the heating was turned on and the temperature was stabilized at 40°C, 1.01 g of NaI was added as a catalyst, and then C4H9ONa was weighed and added rapidly in batches, with a total amount of 2.83 g, and the reaction was carried out for 30 minutes, 17.20 g of methyl chloromethoxylaurate was weighed, and slowly added dropwise under nitrogen protection, and the reaction was carried out for 2 hours. The reaction was quenched with ice water, extracted with ethyl acetate, the upper layer solution was combined and washed twice with saturated brine, and the crude product was obtained by rotary evaporation, the crude product was pulped, recrystallized, filtered, and the mother liquor was obtained, and the mother liquor was subjected to column chromatography, and the chromatographic liquid was rotary evaporated to obtain compound A3, with an HPLC purity of 99.49%.

[0059] Example 5: Preparation of Compound A4 (n=14)

[0060] 10.00 g of epiriprazole was added to 200 mL of tetrahydrofuran, and 2.80 g of C4H9OK was added in batches, and the mixture was reacted for 30 min. 1.02 g of KI was added, and 17.23 g of methyl chloromethoxypalmitate was measured and slowly added dropwise, and the mixture was reacted for 2 h. The reaction was quenched with ice water, and the mixture was extracted with ethyl acetate for 3 times. The upper layer solutions were combined and washed twice with saturated brine, and dehydrated with anhydrous magnesium sulfate, and then the mixture was rotary evaporated, weighed, mixed (1.5 times), and subjected to column chromatography. The chromatographic solution was rotary evaporated to obtain compound A4, and the HPLC purity was 99.32%.

[0061] Example 6: Preparation of Compound A5 (n=16)

[0062] 10.01 g of epiriprazole was added to 200 mL of tetrahydrofuran, 2.83 g of NaH was added in batches, the mixture was reacted for 30 min, 1.00 g of KI was added, 17.23 g of methyl chloromethoxystearate was measured, slowly added dropwise, and the mixture was reacted for 2 h. The reaction was quenched with ice water, extracted with ethyl acetate for 3 times, the upper layer solutions were combined and washed twice with saturated brine, and dehydrated with anhydrous magnesium sulfate, rotary evaporated, weighed, mixed (1.5 times), column chromatographed, and the chromatographic solution was rotary evaporated to obtain compound A5, with an HPLC purity of 99.41%.

[0063] Effect Example 1: Comparative Study on the Metabolism of Compound A1 (n=4) and Epiprazole Laurate in Plasma

[0064] This test example is a comparative test of plasma incubation metabolism of compound A1 and epiriprazole laurate. The specific test steps are as follows:

[0065] (1) Preparation of plasma: Whole blood was collected from SD rats via the eye socket and placed in a vacuum blood collection tube containing sodium heparin. The blood was centrifuged (12000 rpm, 5 min) and the supernatant was taken as plasma.

[0066] (2) Preparation of blank plasma: 100 μL of plasma was placed in a centrifuge tube, 900 μL of methanol was added, vortexed for 3 min, centrifuged (12000 rpm, 5 min), and the supernatant was taken as blank plasma.

[0067] (3) Preparation of drug stock solutions: Accurately weigh appropriate amounts of 16.05 mg of BPZL and 14.93 mg of compound A1 into a 10 mL volumetric flask, add appropriate amount of methanol and sonicate to dissolve, add methanol to make up to the mark, and shake well to obtain the drug stock solutions.

[0068] (4) Preparation of mixed control solution: Accurately pipette 100 μL of each drug stock solution into 500 μL of plasma, add 1 mL of methanol, vortex for 5 min, centrifuge (12000 rpm, 7 min), and take the supernatant to obtain the mixed control solution.

[0069] (5) Preparation of incubation solution: Take 1.5 mL of plasma, add 60 μL of each drug stock solution, vortex for 5 min, and incubate in a shaker (37° C., 100 rpm) to obtain the incubation solution.

[0070] (6) Preparation of detection solution: Take 100 μL of sample at 0 h, 0.5 h, 1 h, 2 h, 3 h, 5 h, 8 h, 12 h, 20 h, and 24 h and put it into a centrifuge tube. Add 900 μL of methanol, vortex for 3 min, centrifuge (12000 rpm, 5 min), take the supernatant, and inject it.

[0071] (7) The chromatographic conditions are as follows:

[0072] Chromatographic column: LP-C18 4.6*250mm 5μm

[0073] Mobile phase: (0.15% triethylamine pH 3.50) Phase A: (pure acetonitrile) Phase B = 1:9

[0074] Running time: 30 minutes

[0075] Injection volume: 10 μL

[0076] Absorption wavelength: 220nm

[0077] Flow rate: 1.5mL / min

[0078] Column temperature: 35°C.

[0079] (8) The results are shown in the following table:

[0080]

[0081] In the table, ND means not detected.

[0082] Effect Example 2: Comparative Study on the Metabolism of Compound A2 (n=8) and Epiprazole Laurate in Plasma

[0083] This test example is a comparative test of plasma incubation metabolism of compound A2 and epiriprazole laurate. The specific test steps are as follows:

[0084] (1) Preparation of plasma: Whole blood was collected from SD rats via the eye socket and placed in a vacuum blood collection tube containing sodium heparin. The blood was centrifuged (12000 rpm, 5 min) and the supernatant was taken as plasma.

[0085] (2) Preparation of blank plasma: 100 μL of plasma was placed in a centrifuge tube, 900 μL of methanol was added, vortexed for 3 min, centrifuged (12000 rpm, 5 min), and the supernatant was taken as blank plasma.

[0086] (3) Preparation of drug stock solutions: Accurately weigh appropriate amounts of BPZL (98.97 mg) and compound A2 (99.74 mg) into 10 mL volumetric flasks, add appropriate amounts of methanol and sonicate to dissolve, add methanol to make up to the mark, and shake well to obtain drug stock solutions.

[0087] (4) Preparation of mixed control solution: Accurately pipette 100 μL of each drug stock solution into 500 μL of plasma, add 1 mL of methanol, vortex for 5 min, centrifuge (12000 rpm, 7 min), and take the supernatant to obtain the mixed control solution.

[0088] (5) Preparation of incubation solution: Take 1 mL of plasma, add 40 μL of each drug stock solution, vortex for 5 min, and incubate in a shaker (37° C., 100 rpm) to obtain the incubation solution.

[0089] (6) Preparation of detection solution: Take 50 μL of sample at 0 min, 10 min, 20 min, 30 min, 60 min, 2 h, 5 h, 8 h, 17 h, 20 h, and 25 h and put it into a centrifuge tube. Add 250 μL of methanol, vortex for 3 min, centrifuge (12000 rpm, 5 min), take the supernatant, and inject it.

[0090] (7) The chromatographic conditions are as follows:

[0091] Chromatographic column: LP-C18 4.6*250mm 5μm

[0092] Mobile phase: (0.15% triethylamine pH 3.50) Phase A: (pure acetonitrile) Phase B = 1:9

[0093] Running time: 30 minutes

[0094] Injection volume: 10 μL

[0095] Absorption wavelength: 220nm

[0096] Flow rate: 1.5mL / min

[0097] Column temperature: 35°C.

[0098] (8) The results are shown in the following table:

[0099]

[0100]

[0101] Effect Example 3. Comparative study on the metabolism of compound A3 (n=10) and epipiprazole laurate in plasma

[0102] This test example is a comparative test of plasma incubation metabolism of compound A3 and epiriprazole laurate. The specific test steps are as follows:

[0103] (1) Preparation of plasma: Whole blood was collected from SD rats via the eye socket and placed in a vacuum blood collection tube containing sodium heparin. The blood was centrifuged (12000 rpm, 5 min) and the supernatant was taken as plasma.

[0104] (2) Preparation of blank plasma: 100 μL of plasma was placed in a centrifuge tube, 900 μL of methanol was added, vortexed for 3 min, centrifuged (12000 rpm, 5 min), and the supernatant was taken as blank plasma.

[0105] (3) Preparation of drug stock solutions: Accurately weigh appropriate amounts of BPZL (16.89 mg) and compound A3 (18.80 mg) into 10 mL volumetric flasks, add appropriate amounts of methanol and sonicate to dissolve, add methanol to make up to the mark, and shake well to obtain drug stock solutions.

[0106] (4) Preparation of mixed control solution: Accurately pipette 100 μL of each drug stock solution into 500 μL of plasma, add 1 mL of methanol, vortex for 5 min, centrifuge (12000 rpm, 7 min), and take the supernatant to obtain the mixed control solution.

[0107] (5) Preparation of incubation solution: Take 1.5 mL of plasma, add 60 μL of each drug stock solution, vortex for 5 min, and incubate in a shaker (37° C., 100 rpm) to obtain the incubation solution.

[0108] (6) Preparation of detection solution: Take 100 μL of sample at 0 h, 0.5 h, 1 h, 2 h, 3 h, 5 h, 8 h, 12 h, 20 h, and 24 h and put it into a centrifuge tube. Add 900 μL of methanol, vortex for 3 min, centrifuge (12000 rpm, 5 min), take the supernatant, and inject it.

[0109] (7) The chromatographic conditions are as follows:

[0110] Chromatographic column: LP-C18 4.6*250mm 5μm

[0111] Mobile phase: (0.15% triethylamine pH 3.50) Phase A: (pure acetonitrile) Phase B = 1:9

[0112] Running time: 30 minutes

[0113] Injection volume: 10 μL

[0114] Absorption wavelength: 220nm

[0115] Flow rate: 1.5mL / min

[0116] Column temperature: 35°C.

[0117] (8) The results are shown in the following table and Figure 2 As shown:

[0118]

[0119] Effect Example 4: Comparative Study on the Metabolism of Compound A3 (n=10) and Epiprazole Laurate in Whole Blood

[0120] This test example is a comparative test of compound A3 and epiriprazole laurate in whole blood incubation metabolism. The specific test steps are as follows:

[0121] (1) Preparation of whole blood: Whole blood of SD rats was collected from the eye socket and placed in a vacuum blood collection tube.

[0122] (2) Preparation of drug stock solutions: Accurately weigh appropriate amounts of BPZL (99.23 mg) and compound A3 (104.52 mg) into a 10 mL volumetric flask, add appropriate amounts of methanol and sonicate to dissolve, add methanol to make up to the mark, and shake well to obtain the drug stock solutions.

[0123] (3) Preparation of mixed control solution: Accurately pipette 100 μL of each drug stock solution into 500 μL of plasma, add 1 mL of methanol, vortex for 5 min, centrifuge (12000 rpm, 7 min), and take the supernatant to obtain the mixed control solution.

[0124] (4) Preparation of incubation solution: Take 1.0 mL of whole blood, add 40 μL of each drug stock solution, vortex for 5 min, and incubate in a shaker (37° C., 100 rpm) to obtain the incubation solution.

[0125] (5) Preparation of detection solution: Take 50 μL of sample at 0 min, 10 min, 20 min, 30 min, 1 h, 2 h, 5 h, 8 h, and 17 h and put it into a centrifuge tube. Add 250 μL of methanol, vortex for 3 min, centrifuge (12000 rpm, 5 min), take the supernatant, and inject it.

[0126] (6) The chromatographic conditions are as follows:

[0127] Chromatographic column: C18 4.6*150mm 5μm

[0128] Mobile phase: (0.15% triethylamine pH 3.50) Phase A: (pure acetonitrile) Phase B = 1:9

[0129] Run time: 15 minutes

[0130] Injection volume: 10 μL

[0131] Absorption wavelength: 220nm

[0132] Flow rate: 1.5mL / min

[0133] Column temperature: 35°C.

[0134] (7) The results are shown in the following table and Figure 1 As shown:

[0135]

[0136]

[0137] Effect Example 5: Comparative Study on the Metabolism of Compound A4 (n=14) and Epiprazole Laurate in Plasma

[0138] This test example is a comparative test of plasma incubation metabolism of compound A4 and epiriprazole laurate. The specific test steps are as follows:

[0139] (1) Preparation of plasma: Whole blood was collected from SD rats via the eye socket and placed in a vacuum blood collection tube containing sodium heparin. The blood was centrifuged (12000 rpm, 5 min) and the supernatant was taken as plasma.

[0140] (2) Preparation of blank plasma: 100 μL of plasma was placed in a centrifuge tube, 900 μL of methanol was added, vortexed for 3 min, centrifuged (12000 rpm, 5 min), and the supernatant was taken as blank plasma.

[0141] (3) Preparation of drug stock solutions: Accurately weigh appropriate amounts of BPZL 120.01 mg and compound A4 137.02 mg into a 10 mL volumetric flask, add appropriate amount of methanol and sonicate to dissolve, add methanol to make up to the mark, and shake well to obtain the drug stock solutions.

[0142] (4) Preparation of mixed control solution: Accurately pipette 10 μL of BPZL stock solution and 15 μL of compound A4 into 500 μL of plasma, add 1 mL of methanol, vortex for 5 min, centrifuge (12000 rpm, 7 min), and collect the supernatant to obtain the mixed control solution.

[0143] (5) Preparation of incubation solution: Take 1.0 mL of plasma, add 40 μL of each drug stock solution, vortex for 5 min, and incubate in a shaker (37° C., 100 rpm) to obtain the incubation solution.

[0144] (6) Preparation of detection solution: 40 μL of sample was taken at 0 min, 10 min, 20 min, 30 min, and 60 min respectively and placed in a centrifuge tube. 240 μL of acetonitrile was added. The mixture was vortexed for 3 min and centrifuged (12000 rpm, 5 min). The supernatant was collected and injected.

[0145] (7) The chromatographic conditions are as follows:

[0146] Chromatographic column: LP-C18 4.6*250mm 5μm

[0147] Mobile phase: (0.15% triethylamine pH 3.50) Phase A: (pure acetonitrile) Phase B = 1:9

[0148] Running time: 30 minutes

[0149] Injection volume: 10 μL

[0150] Absorption wavelength: 220nm

[0151] Flow rate: 1.5mL / min

[0152] Column temperature: 35°C.

[0153] (8) The results are shown in the following table:

[0154]

[0155] Effect Example 6: Comparative Study on the Metabolism of Compound A5 (n=16) and Epiprazole Laurate in Plasma

[0156] This test example is a comparative test of plasma incubation metabolism of compound A5 and epiriprazole laurate. The specific test steps are as follows:

[0157] (1) Preparation of plasma: Whole blood was collected from SD rats via the eye socket and placed in a vacuum blood collection tube containing sodium heparin. The blood was centrifuged (12000 rpm, 5 min) and the supernatant was taken as plasma.

[0158] (2) Preparation of blank plasma: 100 μL of plasma was placed in a centrifuge tube, 900 μL of methanol was added, vortexed for 3 min, centrifuged (12000 rpm, 5 min), and the supernatant was taken as blank plasma.

[0159] (3) Preparation of drug stock solutions: Accurately weigh appropriate amounts of BPZL 125.85 mg and compound A5 148.47 mg into a 10 mL volumetric flask, add appropriate amount of methanol and sonicate to dissolve, add methanol to make up to the mark, and shake well to obtain the drug stock solutions.

[0160] (4) Preparation of mixed control solution: Accurately pipette 15 μL of each drug stock solution into 500 μL of plasma, add 1 mL of methanol, vortex for 5 min, centrifuge (12000 rpm, 7 min), and take the supernatant to obtain the mixed control solution.

[0161] (5) Preparation of incubation solution: Take 1.0 mL of plasma, add 40 μL of each drug stock solution, vortex for 5 min, and incubate in a shaker (37° C., 100 rpm) to obtain the incubation solution.

[0162] (6) Preparation of detection solution: 40 μL of sample was taken at 0 min, 10 min, 20 min, 30 min, 60 min, and 120 min respectively and placed in a centrifuge tube. 260 μL of acetonitrile was added. The mixture was vortexed for 3 min and centrifuged (12000 rpm, 5 min). The supernatant was collected and injected.

[0163] (7) The chromatographic conditions are as follows:

[0164] Chromatographic column: LP-C18 4.6*250mm 5μm

[0165] Mobile phase: (0.15% triethylamine pH 3.50) Phase A: (pure acetonitrile) Phase B = 1:9

[0166] Running time: 30 minutes

[0167] Injection volume: 10 μL

[0168] Absorption wavelength: 220nm

[0169] Flow rate: 1.5mL / min

[0170] Column temperature: 35°C.

[0171] (8) The results are shown in the following table:

[0172]

[0173]

[0174] The above in vitro metabolism experiments show that the final metabolite of the compound of the present invention in plasma or whole blood is epiriprazole, and the metabolic rate is faster than epiriprazole laurate.

Claims

1. Epiprazole methyl fatty acid ester and its pharmaceutically acceptable salt as shown in formula I: Formula I in, n is an integer from 4 to 16.

2. The epiprazole methyl fatty acid ester and its pharmaceutically acceptable salt as shown in formula I according to claim 1, characterized in that: n is 4, 8, 10, 14 or 16.

3. A method for preparing the epipiprazole methyl fatty acid ester as shown in formula I, comprising the following steps: In a solvent, under the action of a base and a catalyst, the compound represented by formula II reacts with the compound represented by formula III to obtain epipiprazole methyl fatty acid ester represented by formula I; in, X is halogen, and n is as defined in claim 1 or 2.

4. The method for preparing the epiprazole methyl fatty acid ester as shown in formula I as claimed in claim 3, characterized in that: X is Cl or Br.

5. The method for preparing the epiprazole methyl fatty acid ester as shown in formula I as claimed in claim 3, characterized in that: X is Cl.

6. The method for preparing the epiprazole methyl fatty acid ester as shown in formula I as claimed in claim 3, characterized in that: The preparation method meets one or more of the following conditions: (1) The molar ratio of the compound represented by formula II to the compound represented by formula III is 1:(2-4); (2) The solvent is an ether solvent; (3) The volume mass ratio of the solvent to the compound represented by Formula II is (15-25) mL / g; (4) The base is one or more of sodium ethoxide, sodium hydrogen hydrate, sodium methoxide, sodium tert-butoxide and potassium tert-butoxide; (5) The mass ratio of the base to the compound represented by formula II is (0.25-0.32):1; (6) The catalyst is potassium iodide and / or sodium iodide; (7) The mass ratio of the catalyst to the compound represented by formula II is (0.05-0.15): 1; (8) The reaction temperature is 35-50°C; (9) The reaction time is 1.5-4 hours.

7. The method for preparing the epiprazole methyl fatty acid ester as shown in formula I as claimed in claim 3, characterized in that: The preparation method meets one or more of the following conditions: (1) The molar ratio of the compound represented by formula II to the compound represented by formula III is 1:3; (2) The solvent is tetrahydrofuran and / or dioxane; (3) The volume mass ratio of the solvent to the compound represented by Formula II is 20 mL / g; (4) The mass ratio of the base to the compound represented by formula II is 0.28:1; (5) The mass ratio of the catalyst to the compound represented by formula II is 0.1:1; (6) The reaction time is 2.5 hours.

8. The method for preparing the epiprazole methyl fatty acid ester as shown in formula I according to any one of claims 3 to 7, characterized in that: The preparation method of the epiprazole methyl fatty acid ester as shown in formula I comprises the following steps: in a solvent, the compound as shown in formula II is first reacted with a base, and then reacted with a compound as shown in formula III under the action of a catalyst.

9. The method for preparing the epiprazole methyl fatty acid ester as shown in formula I as claimed in claim 3, characterized in that: The preparation method of the epiprazole methyl fatty acid ester as shown in Formula I further comprises the following post-treatment steps: quenching the reaction with water, extracting with an organic solvent, combining the organic phases, concentrating and then performing column chromatography.

10. The method for preparing the epiprazole methyl fatty acid ester as shown in formula I according to claim 9, characterized in that: In the post-treatment step, the water is ice water; and the organic solvent is ethyl acetate.

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