Lumateperone intermediate and preparation method therefor

Abstract

The present invention relates to a lumateperone intermediate and a preparation method therefor. Specifically, the present invention provides a novel intermediate compound of formula I in a crystalline form, a preparation method therefor, and the use thereof in the preparation of lumateperone tosylate. After the compound of formula I is obtained, the compound of formula I is reacted with a compound of formula III to obtain a compound of formula IV, and then the compound of formula IV and p-toluenesulfonic acid form a salt to obtain lumateperone tosylate. The reaction route has the advantages of high yield, low cost, suitability for industrial production and the like.

Description

Lumepiride intermediate and its preparation method Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry and relates to an intermediate compound for preparing lumepirozon tosylate and its preparation method. Background Technology

[0002] Lumepiride tosylate, developed by Intra-Cellular Therapies, Inc., is a novel drug for the treatment of schizophrenia. Marketed under the brand name Caplyta, it was approved by the FDA on December 20, 2019, for the treatment of schizophrenia in adults. In December 2021, a new indication was added for the treatment of bipolar I or II-related depressive episodes in adults. The chemical structure of lumepimepiride tosylate is shown below:

[0003] Currently, there are several main synthetic routes for rumepiride:

[0004] The route reported in patent application WO0077001, as shown in Scheme 1, involves N-alkylating a racemic cis-II compound with a haloketone III to obtain a racemic free base compound V. The target product, lumepirolen free base, is then obtained by chiral HPLC separation. The final step of this route uses HPLC to separate the target product, resulting in low raw material utilization and low yield, which is not conducive to industrial production.

[0005] The route reported in patent application WO2019102240A1 and document Tetrahedron 120 (2022), 132862, as shown in Scheme 2, involves reacting the racemic cis compound 6 with a chiral resolving agent 12 to form a salt, followed by resolving the compound 13. This salt is then acidified to give compound 14, which is subsequently reacted with compound 7 and p-toluenesulfonic acid to yield compound 15, lumepiromium toluenesulfonic acid. The disadvantages of this route are that the chiral resolving agent 12 is a non-natural raw material, requiring at least two reaction steps for preparation and purification, resulting in high costs and low resolving yields. Furthermore, the use of highly corrosive and volatile hydrogen chloride places high demands on the reaction equipment.

[0006] The route reported in patent application WO2020112941A2, as shown in scheme 3, involves resolving racemic compound 6 under alkaline conditions using the resolving agent L-di-p-methylbenzoyl-tartaric acid (L-DTTA), followed by reaction with compound 7 to obtain the free base of lumepirobenone. The resolving agent L-DTTA used in this route is not a natural raw material and requires 1-2 steps of chemical synthesis. Furthermore, due to its large molecular weight, the amount of this resolving agent used is large, resulting in high cost and a low resolving yield (40%).

[0007] Therefore, in summary, the currently reported synthetic routes for lumepirozon mainly employ chiral HPLC columns or non-natural resolving agents for intermediate resolution. However, these non-natural resolving agents require synthetic preparation, which is costly, and their yields in the resolution reactions are low. Therefore, it is necessary to develop new synthetic methods for lumepirozon to avoid these drawbacks. Summary of the Invention

[0008] To overcome the shortcomings of existing technologies, this invention provides a novel method for synthesizing lumepirozol and a novel intermediate compound. This method is characterized by its ease of operation, readily available and inexpensive raw materials, high product yield, and good purity of the intermediate and target product, and is easily applicable to industrial production.

[0009] In a first aspect, the present invention provides an intermediate compound of formula I, the structure of which is as follows:

[0010] Where n = 0 or 1.

[0011] In one embodiment, the compound of formula I is a crystalline compound.

[0012] When n = 0, it is a compound of formula IA; when n = 1, it is a compound of formula 1B.

[0013] In one embodiment, the compounds of formula IA and formula IB provided by the present invention are both crystalline compounds.

[0014] The characteristic of the IA crystalline compound is that, when powder X-ray diffraction analysis is performed using CuKα-ray experimental conditions, its PXRD pattern exhibits characteristic diffraction signal peaks at 2θ angles of 5.7±0.2°, 13.4±0.2°, and 17.7±0.2°.

[0015] More preferably, the IA crystalline compound is characterized in that, when powder X-ray diffraction analysis is performed using CuKα-ray experimental conditions, its PXRD pattern exhibits characteristic diffraction signal peaks at 2θ angle positions of 5.7±0.2°, 13.4±0.2°, 16.8±0.2°, 17.7±0.2°, 18.9±0.2°, and 23.6±0.2°.

[0016] More preferably, the IA crystalline compound is characterized in that, when powder X-ray diffraction analysis is performed using CuKα-ray experimental conditions, its PXRD pattern exhibits characteristic diffraction signal peaks at 2θ angle positions of 5.7±0.2°, 10.5±0.2°, 13.4±0.2°, 16.8±0.2°, 17.7±0.2°, 18.9±0.2°, 19.7±0.2°, 23.6±0.2°, and 28.3±0.2°.

[0017] The PXRD data of the IA crystalline compound are as follows.

[0018] In a more preferred embodiment, the crystal of compound IA has a PXRD pattern as shown in FIG1.

[0019] The characteristic of the IB crystalline compound is that, when powder X-ray diffraction analysis is performed using CuKα-ray experimental conditions, it exhibits characteristic diffraction signal peaks at 2θ angle positions of 12.7±0.2°, 16.6±0.2°, 18.0±0.2°, and 22.0±0.2°.

[0020] More preferably, the IB crystal compound is characterized by exhibiting characteristic diffraction signal peaks at 2θ angle positions of 12.7±0.2°, 15.7±0.2°, 16.6±0.2°, 18.0±0.2°, 22.0±0.2°, 22.2±0.2° and 23.8±0.2° when subjected to powder X-ray diffraction analysis under CuKα-ray experimental conditions.

[0021] More preferably, the IB crystalline compound is characterized by exhibiting characteristic diffraction signal peaks at 2θ angles of 9.4±0.2°, 12.7±0.2°, 15.7±0.2°, 16.6±0.2°, 18.0±0.2°, 22.0±0.2°, 22.2±0.2°, 23.8±0.2°, and 25.7±0.2° when subjected to powder X-ray diffraction analysis under CuKα-ray experimental conditions.

[0022] The PXRD data of this IB crystalline compound are as follows.

[0023] In a more preferred embodiment, the crystal of the IB compound has a PXRD pattern as shown in FIG2.

[0024] Figures 3 and 4 are the positive and negative ion mode mass spectra of the compound of formula IB. Figure 3 shows the positive ion molecular ion peak (M+H). +The value is 230.1665, which is a single molecule of compound II; Figure 4 shows the molecular ion peak (MH) of the negative ion. + The value is 149.0092, which is one molecule of D-tartaric acid; this proves that one molecule of compound IB contains one molecule of compound II and one molecule of D-tartaric acid.

[0025] Figure 5 shows the proton NMR spectrum of compound IB, and Figure 6 shows the carbon NMR spectrum of compound IB. The two hydrogen atoms at chemical shift 4.07 ppm in the proton NMR spectrum represent the characteristic peaks of hydrogen atoms on the two chiral carbon atoms of the D-tartaric acid molecule in compound IB. The chemical shift at 175.0 ppm in the carbon NMR spectrum represents the two carbon atoms on the carboxyl group of the D-tartaric acid molecule in compound IB, and chemical shifts of 72.3 ppm and 72.5 ppm correspond to the two middle carbon atoms. This indicates that one molecule of compound IB contains one molecule of D-tartaric acid.

[0026] Figure 7 shows the TGA spectrum of compound IB. The spectrum shows a broad endothermic peak for solvent removal before 200 °C, with solvent removal starting at approximately 130.5 °C and all solvent lost at 178.08 °C. The weight loss is 4.50%, which is basically consistent with the water content of 4.53% in compound IB, proving that one molecule of compound IB contains one water molecule.

[0027] The single-crystal structure data of the IB compound of the present invention are shown in Table 1, and the non-hydrogen atom coordinates and temperature factors of the IB compound molecule are shown in Table 2.

[0028] Table 1: Single-crystal structure data and structure correction data of compounds of formula IB

[0029] Table 2: Atomic coordinates and temperature factors of non-hydrogen atoms

[0030] Crystal structure analysis results indicate that the compound of formula IB belongs to the orthorhombic crystal system, space group P212121(19#), and its unit cell parameters are: Z = 4, molecular formula: C 14 H 20The molecular structure of N3·C4H5O6·H2O is shown in Figure 8 (systematic name: (6bR,10as)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4:4,5]pyrrole[1,2,3-de]quinoxaline(2s,3S)-2,3-dihydroxysuccinate monohydrate). Its smallest asymmetric unit contains a cation of formula II, a succinate anion, and a water molecule. A carboxyl hydrogen atom of succinate is transferred to the octahydropyridine nitrogen atom of formula II, forming the succinate hydrate of formula II. Atom numbering is shown in Figure 9. The unimolecular structure contains four chiral carbon atoms, with C11 in the "R" configuration and C10, C16, and C17 in the "S" configuration. The molecular configuration diagram is shown in Figure 10. In the structure, formula II and succinic acid are linked by hydrogen bonds, and then form a two-dimensional layered structure that extends infinitely along the ab plane through hydrogen bonds between succinic acid and water molecules (Figure 11). The layers are stacked parallel to each other along the c direction to form a three-dimensional stacked structure (Figure 12).

[0031] Secondly, the present invention provides a method for preparing a compound of formula I, comprising the following steps:

[0032] The compound of formula II is reacted with D-tartaric acid in an organic solvent or in a mixture of an organic solvent and water to give the compound of formula I.

[0033] Where n = 0 or 1.

[0034] In one embodiment, the preparation method of compound I includes: adding compound II and D-tartaric acid to an organic solvent and heating to dissolve them, or adding them to a mixture of organic solvent and water and heating to dissolve them, cooling to crystallize, filtering and drying to obtain compound I. When the reaction solution does not contain water, compound IA is obtained; when the reaction solution contains water, compound IB is obtained.

[0035] The organic solvent is selected from any one of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, acetone, butanone, toluene, acetonitrile, diethyl ether, isopropyl ether, methyl tert-butyl ether, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran, DMF, DMA, NMP and DMSO, or a mixture of two or more solvents.

[0036] There are no special requirements for the water used, including purified water and tap water; there are also no specific restrictions on the amount of water used, as long as it is sufficient to dissolve and crystallize the compound.

[0037] The molar ratio of the compound of formula II to D-tartaric acid is 1:1.0-5.0.

[0038] The dissolution temperature is 40-130℃, and the crystallization temperature is 0-50℃.

[0039] The drying process is either vacuum drying or atmospheric pressure drying, and the drying temperature is between 20°C and 100°C.

[0040] Thirdly, the present invention provides a method for preparing lumepirozol tosylate, comprising the following steps:

[0041] Step 1: In the presence of a base, react the compound of formula I with the compound of formula III to obtain the compound of formula IV;

[0042] Step 2: Compound IV reacts with p-toluenesulfonic acid to form a salt, yielding lumepirozon p-toluenesulfonic acid; and

[0043] Optionally, the product from step 2 may be further purified by crystallization.

[0044] Generally, step 1 includes reacting the compound of formula I, the compound of formula III, the base, and the iodide in an organic solvent or a mixture of an organic solvent and water to obtain the compound of formula IV. In one embodiment, the compound of formula I, the compound of formula III, the base, and the iodide are added to an organic solvent or a mixture of an organic solvent and water, heated and stirred until dissolved, and reacted for 8-24 hours. After the reaction is complete, the reaction is quenched with water by cooling, the pH is adjusted to weakly alkaline by adding acid, extracted with an organic solvent, washed with water, and concentrated under reduced pressure to obtain the compound of formula IV.

[0045] The base is selected from inorganic or organic bases, such as one or more bases selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, disodium hydrogen phosphate, sodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, triethylamine, pyridine, 2,6-dimethylpyridine, DIPEA, DBU and N,N-dimethylaniline.

[0046] The iodide is selected from sodium iodide, potassium iodide and tetrabutylammonium iodide.

[0047] The reaction is carried out in an organic solvent or a mixture of an organic solvent and water, wherein the organic solvent is selected from one, two, or a mixture of two or more solvents selected from: butanone, 3-pentanone, methyl isobutyl ketone, methanol, ethanol, isopropanol, water, acetonitrile, DMF, DMA, DMSO, NMP, toluene, benzene, ethyl acetate, isopropyl acetate, butyl acetate, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, isopropyl ether, and ethylene glycol dimethyl ether.

[0048] In step 2, the molar ratio of the compound of formula IV to D-tartaric acid is 1:1-2.

[0049] The reaction temperature is 40-100℃.

[0050] In step 2, the compound of formula IV reacts with p-toluenesulfonic acid to form a salt to obtain lumepirozoline p-toluenesulfonic acid. In one embodiment, the compound of formula IV and p-toluenesulfonic acid are added to an organic solvent, heated to dissolve, cooled to crystallize, filtered, and dried to obtain lumepirozoline p-toluenesulfonic acid.

[0051] The organic solvent is selected from one or a mixture of two or more of the following: methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, butyl acetate, acetonitrile, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, water, butanone, 3-pentanone, methyl isobutyl ketone, DMF, DMA, DMSO, NMP, toluene, benzene, and xylene.

[0052] The dissolution temperature is 20-80℃.

[0053] The crystallization temperature is -10 to 60°C.

[0054] The vacuum drying temperature is 20-80℃, and the drying time is 1-20 hours.

[0055] Optionally, the product from step 2 may be further purified by crystallization. The purification conditions are as described in step 2.

[0056] In a preferred embodiment, the method for preparing lumepirozoline tosylate according to the third aspect further includes the step of preparing compound I according to the second aspect.

[0057] In one specific implementation, the method for preparing lumepirozoline tosylate according to the third aspect comprises the following steps, wherein the reaction conditions for each step are as described above:

[0058] Where n = 0 or 1. Attached Figure Description

[0059] Figure 1: PXRD pattern of compound IA.

[0060] Figure 2: PXRD pattern of compound IB.

[0061] Figure 3: Mass spectrum (positive ion mode) of compound IB.

[0062] Figure 4: Mass spectrum of compound IB (negative ion mode).

[0063] Figure 5: The proton spectrum of compound IB.

[0064] Figure 6: Carbon spectrum of compound IB.

[0065] Figure 7: TGA spectrum of compound IB.

[0066] Figure 8: Schematic diagram of the molecular structure of compound IB.

[0067] Figure 9: Molecular thermal ellipsoid diagram of the crystal of compound IB (ORTEP diagram, ellipsoid probability 50%).

[0068] Figure 10: Molecular configuration of compound IB (hydrogen atoms, which are non-chiral atoms, are not shown).

[0069] Figure 11: Two-dimensional layered structure diagram of compound IB.

[0070] Figure 12: Three-dimensional packing structure diagram of compound IB. Detailed Implementation

[0071] The method of the present invention will be further illustrated by the following embodiments. It should be understood that the purpose of providing the following embodiments is merely to enable a better understanding of the present invention, and not to limit the scope of the present invention in any way.

[0072] Example 1: Preparation of Compound II

[0073] Under nitrogen protection, 400g of n-butanol, 56g of potassium hydroxide, and 100g of compound V were added sequentially to a reaction vessel. The mixture was heated to 90-100℃ and reacted for 8-12 hours. After cooling to room temperature, the reaction solution was quenched in water. The mixture was extracted three times with ethyl acetate, washed once with water, and evaporated to dryness to obtain 79.2g of compound II, with a yield of 99.2%.

[0074] 1H NMR (500MHz, CDCl3) δ6.72-6.58(m,1H),6.57-6.44(m,1H),6.44-6.33(m,1H),3.61-3.49(m,1H),3.38-3.21(m,3H) ,3.13-2.93(m,2H),2.89-2.85(m,3H),2.85-2.77(m,3H),2.67-2.54(m,1H),1.96-1.80(m,1H),1.80-1.64(m,1H).

[0075] Example 2: Preparation of Compound IB

[0076] Under nitrogen protection, 1000g of ethanol, 45g of water, 150g of compound II and 119g of D-tartaric acid were added sequentially to a reaction vessel. The mixture was heated to reflux until dissolved, cooled to room temperature, and stirred for 1.0-2.0 hours. After filtration and drying, 117g of compound IB was obtained with a chiral purity of 99.8% and a yield of 45.0%.

[0077] 1 H NMR (500MHz, DMSO) δ6.57(t,J=7.6Hz,1H),6.47(d,J=7.1Hz,1H),6.39(d,J=7.6 Hz,1H),4.25-3.87(m,2H),3.53-3.40(m,1H),3.36(dd,J=7.6,2.7Hz,1H),3.32 -3.21(m,3H),3.16(dd,J=9.1,3.0Hz,2H),2.91(td,J=12.3,4.4Hz,1H),2.82-2 .73(m,3H),2.68(td,J=10.1,2.7Hz,1H),2.49-2.37(m,1H),2.14-1.94(m,2H).

[0078] 13 C NMR(126MHz,DMSO)δ175.44(s),137.85(s),135.62(s),128.01(s),120.90(s),112.87(s),109.63( s),72.76(s),63.24(s),50.29(s),44.44(d,J=71.0Hz),39.11(s),37.94(s),37.49(s),21.30(s).

[0079] Example 3: Preparation of Compound IB

[0080] Under nitrogen protection, 1100g methanol, 50g water, 150g compound II, and 110g D-tartaric acid were added sequentially to a reaction vessel. The mixture was heated to reflux until dissolved, then cooled to 0°C and held at that temperature for 1.0-3.0 hours. After filtration and drying, 120.9g compound IA was obtained with a chiral purity of 99.7% and a yield of 46.5%.

[0081] Example 4: Preparation of Compound IB

[0082] Under nitrogen protection, 600g of tetrahydrofuran, 30g of water, 75g of compound II, and 50.5g of D-tartaric acid were added sequentially to a reaction vessel. The mixture was heated to reflux until dissolved, then cooled to 40°C and held at that temperature for 3 hours. After filtration and drying, 56.7g of compound IA was obtained with a chiral purity of 99.8% and a yield of 43.6%.

[0083] Example 5: Preparation of compound IA

[0084] Under nitrogen protection, 250g of methanol, 35g of compound II, and 23.5g of D-tartaric acid were added sequentially to a reaction vessel. The mixture was heated to 65°C and stirred until dissolved. Then, the mixture was cooled to 0°C and kept at that temperature for 2.0-3.0 hours. After filtration and drying, 25.5g of compound IA was obtained with a chiral purity of 99.6% and a yield of 44.0%.

[0085] 1 H NMR (500MHz, DMSO) δ6.57(t,J=7.6Hz,1H),6.47(d,J=7.1Hz,1H),6.39(d,J=7.6 Hz,1H),4.25-3.87(m,2H),3.53-3.40(m,1H),3.36(dd,J=7.6,2.7Hz,1H),3.32 -3.21(m,3H),3.16(dd,J=9.1,3.0Hz,2H),2.91(td,J=12.3,4.4Hz,1H),2.82-2 .73(m,3H),2.68(td,J=10.1,2.7Hz,1H),2.49-2.37(m,1H),2.14-1.94(m,2H).

[0086] 13 C NMR(126MHz,DMSO)δ175.44(s),137.85(s),135.62(s),128.01(s),120.90(s),112.87(s),109.63( s),72.76(s),63.24(s),50.29(s),44.44(d,J=71.0Hz),39.11(s),37.94(s),37.49(s),21.30(s).

[0087] Example 6: Preparation of compound IA

[0088] Under nitrogen protection, 300g of isopropanol, 35g of compound II, and 25.2g of D-tartaric acid were added sequentially to a reaction vessel. The mixture was heated to reflux until dissolved, then cooled to 7-12℃ and stirred for 1.5-2.5 hours. After filtration and drying, 25.0g of compound IB was obtained with a chiral purity of 99.7% and a yield of 43.2%.

[0089] Example 7: Moisture Test of Compound IB

[0090] Instruments and reagents for determining moisture content using the Karl Fischer method (KF method): moisture analyzer, 1 / 100,000 balance, Karl Fischer titrant (5 mg / mL), and anhydrous methanol (analytical grade);

[0091] Moisture determination of sample: Pump an appropriate amount of anhydrous methanol into the titration cup to submerge the electrode (50 mL), take about 0.2 g of the test sample, accurately weigh it into the titration cup, stir to dissolve, and determine the moisture content according to the moisture determination method; perform three parallel operations, and take the average value as the moisture content result.

[0092] Experimental conclusion: The Karl Fischer moisture content was 4.56%, which is basically consistent with the theoretical moisture content of 4.53% in the IB compound, proving that one IB compound contains one water molecule.

[0093] Example 8: Preparation of Compound IV

[0094] Under nitrogen protection, 32 g of 3-pentanone, 2.0 g of compound IB, 2.5 g of sodium carbonate, 0.4 g of potassium iodide, and 1.51 g of 4-chloro-4'-fluorophenylbutanone were added sequentially to a reaction vessel. The mixture was heated to 80 °C and reacted for 10-12 hours. The mixture was then cooled and quenched with water, resulting in separation of the phases. The pH of the organic phase was adjusted to a weakly alkaline state by adding dilute hydrochloric acid. The mixture was extracted with 80 g × 2 methyl tert-butyl ether, washed with 75 g of tap water, and concentrated under reduced pressure to obtain 1.89 g of product compound IV with a purity of 95.0%, a chiral purity of 99.9%, and a yield of 95.5%.

[0095] Example 9: Preparation of Compound IV

[0096] Under nitrogen protection, 40 ml of butanone, 2.0 g of compound IB, 3.5 g of potassium carbonate, 0.38 g of sodium iodide, and 1.5 g of 4-chloro-4'-fluorophenylbutanone were added sequentially to a reaction vessel. The mixture was heated to 80 °C and reacted for 12 hours. After cooling, the mixture was quenched with water, and the layers separated. The pH of the organic phase was adjusted to acidic by adding dilute hydrochloric acid. The mixture was extracted three times with methyl tert-butyl ether, and the pH was adjusted to weakly alkaline. The mixture was then extracted with ethyl acetate, washed with water, dried, and concentrated to obtain 1.88 g of product IB, with a purity of 96.1%, a chiral purity of 99.8%, and a yield of 95.0%.

[0097] Example 10: Preparation of Formula IV compound:

[0098] Under nitrogen protection, 32 g of ethanol, 2.0 g of compound IB, 4.5 g of potassium phosphate, 0.9 g of tetrabutylammonium iodide, and 1.5 g of 4-chloro-4'-fluorophenylbutanone were added sequentially to a reaction vessel. The mixture was heated to 70-80 °C and reacted for 20 hours. The mixture was then cooled and quenched with water. Ethyl acetate was added for extraction, and the layers were separated. The pH of the organic phase was adjusted to acidic by adding dilute hydrochloric acid. The mixture was extracted three times with methyl tert-butyl ether, and the pH was adjusted to weakly alkaline. The mixture was then extracted with methyl tert-butyl ether, washed with water, dried, and concentrated to obtain 1.65 g of product 9 with a purity of 97.0%, a chiral purity of 100%, and a yield of 83.3%.

[0099] Example 11: Preparation of Compound IV:

[0100] Under nitrogen protection, 40 ml of toluene, 20 ml of water, 1.95 g of compound IA, 1.0 g of sodium hydroxide, 0.4 g of potassium iodide, and 1.4 g of 4-chloro-4'-fluorophenylbutanone were added sequentially to a reaction vessel. The mixture was heated to 70-80 °C and reacted for 24 hours. The mixture was then cooled and quenched with water, resulting in separation of the phases. The pH of the organic phase was adjusted to acidic by adding dilute hydrochloric acid. The mixture was extracted three times with isopropyl ether, and the pH was adjusted to weakly alkaline. The mixture was then extracted with toluene, washed with water, dried, and concentrated to obtain 1.72 g of product IV with a purity of 94.0%, a chiral purity of 99.9%, and a yield of 86.9%.

[0101] Example 12: Preparation of Compound IV:

[0102] Under nitrogen protection, 50 ml of DMF, 20 ml of water, 2.0 g of compound IB, 1.1 g of cesium carbonate, 0.09 g of sodium iodide, and 1.5 g of 4-chloro-4'-fluorophenylbutanone were added sequentially to a reaction vessel. The mixture was heated to 70-80 °C and reacted for 12 hours. After cooling, ethyl acetate was added for extraction and separation. The organic phase was adjusted to acidic pH with dilute hydrochloric acid, extracted three times with methyl tert-butyl ether, and the pH was adjusted to weakly alkaline. The mixture was then extracted with dichloromethane, washed with water, dried, and concentrated to obtain 1.56 g of product IB, with a purity of 97.0%, a chiral purity of 99.7%, and a yield of 78.8%.

[0103] Example 13: Preparation of Formula IV compound:

[0104] Under nitrogen protection, 60 ml of DMF, 1.95 g of compound IA, 3.0 g of potassium carbonate, 0.42 g of potassium iodide, and 1.5 g of 4-chloro-4'-fluorophenylbutanone were added sequentially to a reaction vessel. The mixture was heated to 70-80 °C and reacted for 2 days. The reaction was then cooled and quenched with water. Ethyl acetate was added for extraction, and the mixture was separated into layers. The pH of the organic phase was adjusted to acidic by adding dilute hydrochloric acid. The mixture was extracted three times with methyl tert-butyl ether, and the pH was adjusted to weakly alkaline. The mixture was then extracted with methyl tert-butyl ether, washed with water, dried, and concentrated to obtain 1.65 g of product IV with a purity of 96.9%, a chiral purity of 99.8%, and a yield of 83.3%.

[0105] Example 14: Preparation of lumepirozon tosylate:

[0106] Under nitrogen protection, 10 ml of isopropanol and 1.0 g of compound IV were added sequentially to the reaction vessel. After stirring and dissolving, 0.48 g of p-toluenesulfonic acid was added. After the addition was complete, the mixture was stirred for 2 hours and filtered to obtain 1.3 g of white solid product lumepirozoline, with a yield of 90.4%, chiral purity of 100%, and HPLC purity of 99.7%.

[0107] 1H NMR(500MHz,DMSO)δ9.14(br,1H),8.18-7.88(m,2H),7.54-7.43(m,2H),7.43-7.31(m,2H),7.11(d,J=7 .8Hz,2H),6.60(t,J=7.7Hz,1H),6.53(dd,J=17.0,7.2Hz,1H),6.42(d,J=7.8Hz,1H),3.59(dd,J=12.0,6 .4Hz,1H),3.52-3.38(m,3H),3.31(dd,J=6.7,4.8Hz,2H),3.25-2.96(m,6H),2.88-2.76(m,3H),2.70(tt ,J=10.8,5.3Hz,1H),2.64-2.52(m,1H),2.28(s,3H),2.24(s,1H),2.17-2.05(m,1H),2.05-1.88(m,2H).

[0108] Example 15: Preparation of lumepirozon tosylate:

[0109] Under nitrogen protection, isopropyl acetate (20 ml) and compound IV (2.0 g, 1.0 eq) were added sequentially to a reaction vessel. After stirring and dissolving, p-toluenesulfonic acid (0.96 g, 1.0 eq) was added. After the addition was complete, the mixture was stirred for 2 hours and filtered to obtain 2.7 g of white solid product lumepirozoline, with a yield of 93.9%, chiral purity of 100%, and HPLC purity of 99.8%.

[0110] The specific implementation schemes and embodiments described above further illustrate the purpose, technical solution, and beneficial effects of the present invention. It should be understood that the specific implementation schemes and embodiments described above are merely illustrative examples of the present invention and are not intended to limit the scope of the present invention. Any modifications, equivalent substitutions, improvements, etc., made to the implementation schemes within the spirit and principles of the present invention should be included within the protection scope of this application.

Claims

1. Compounds of Formula I: Where n is 0 or 1.

2. The compound according to claim 1, wherein it is a crystalline compound, wherein: When n = 0, it is a compound of formula IA; when n = 1, it is a compound of formula IB, with the following structure:

3. The compound according to claim 2, wherein it is a compound of formula IA, characterized in that... Its powder X-ray diffraction pattern has characteristic diffraction peaks at the following 2θ angles (°): 5.7±0.2°, 13.4±0.2° and 17.7±0.2°.

4. The compound according to claim 3, characterized in that... Its powder X-ray diffraction pattern has characteristic diffraction peaks at the following 2θ angles (°): 5.7±0.2°, 13.4±0.2°, 16.8±0.2°, 17.7±0.2°, 18.9±0.2° and 23.6±0.2°.

5. The compound according to claim 2, wherein it is a compound of formula IB, characterized in that... Its powder X-ray diffraction pattern has characteristic diffraction peaks at the following 2θ angles (°): 12.7±0.2°, 16.6±0.2°, 18.0±0.2° and 22.0±0.2°.

6. The compound according to claim 5, characterized in that... Its powder X-ray diffraction pattern has characteristic diffraction peaks at the following 2θ angles (°): 12.7±0.2°, 15.7±0.2°, 16.6±0.2°, 18.0±0.2°, 22.0±0.2°, 22.2±0.2° and 23.8±0.2°.

7. A method for preparing a compound of formula I according to any one of claims 1-6, the method comprising reacting a compound of formula II with D-tartaric acid in an organic solvent or in a mixture of an organic solvent and water to obtain a compound of formula I; Preferably, the method includes adding D-tartaric acid and the compound of formula II to an organic solvent or a mixture of an organic solvent and water, heating to dissolve, then cooling to crystallize, filtering, and obtaining the compound of formula I.

8. The method according to claim 7, wherein the organic solvent is selected from any one of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, acetone, butanone, toluene, acetonitrile, diethyl ether, isopropyl ether, methyl tert-butyl ether, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran, DMF, DMA, NMP and DMSO, or a mixture of two or more solvents.

9. The method according to claim 7 or 8, wherein the crystallization temperature is 0-50°C.

10. A method for preparing lumepirozon tosylate, comprising the following steps: Step 1: In the presence of a base, react the compound of formula I with the compound of formula III to obtain the compound of formula IV; Step 2: Compound IV reacts with p-toluenesulfonic acid to form a salt, yielding lumepirozon p-toluenesulfonic acid; as well as Optionally, the product from step 2 may be further purified by crystallization.

11. The method according to claim 10, wherein the base in step 1 is selected from inorganic or organic bases, such as one, two, or more bases selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, disodium hydrogen phosphate, sodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, triethylamine, pyridine, 2,6-dimethylpyridine, DIPEA, DBU, and N,N-dimethylaniline.

12. The method according to any one of claims 10 or 11, wherein the reaction in step 1 is carried out in an organic solvent or a mixture of an organic solvent and water, wherein the organic solvent is selected from one, two, or a mixture of two or more of the following: butanone, 3-pentanone, methyl isobutyl ketone, methanol, ethanol, isopropanol, water, acetonitrile, DMF, DMA, DMSO, NMP, toluene, benzene, ethyl acetate, isopropyl acetate, butyl acetate, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, isopropyl ether, and ethylene glycol dimethyl ether.

13. The method according to any one of claims 10-12, wherein in step 2, the molar ratio of the compound of formula IV to D-tartaric acid is 1:1-2.

14. The method according to any one of claims 10-13, wherein the solvent used in step 2 is selected from one, two, or a mixture of two or more solvents selected from methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, butyl acetate, acetonitrile, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, water, butanone, 3-pentanone, methyl isobutyl ketone, DMF, DMA, DMSO, NMP, toluene, benzene, and xylene.

15. The method according to any one of claims 10-14, wherein the method further comprises the step of preparing the compound of formula I according to any one of claims 7-9.

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