Preparation method of hydrobromic acid vortioxetine intermediate

Abstract

The invention relates to a preparation method of a hydrobromic acid vortioxetine intermediate I. The method has the advantages of short steps, environmental friendliness, simplicity in operation, safety, high total yield, mild reaction, low cost and high economic benefit, is more suitable for industrial production, and has a very good application prospect.

Description

Technical Field

[0001] The invention relates to the field of medicine, and in particular to a method for preparing an intermediate of an antidepressant drug, vortioxetine hydrobromide. Background Art

[0002] Vortioxetine hydrobromide, chemically known as 1-[2-(2,4-dimethyl-phenylthio)-phenyl]-piperazine hydrobromide, is the first antidepressant with multiple pharmacodynamic activities. It was jointly developed by Takeda Pharmaceutical Co., Ltd. of Japan and Lundbeck Pharmaceuticals Ltd. of Denmark and was launched in Europe in October 2013 for the treatment of major depressive disorder in adults.

[0003]

[0004] Compound I is a key intermediate for preparing vortioxetine hydrobromide, and the specific preparation route is as follows:

[0005]

[0006] At present, there are few reports on the synthesis of the intermediate compound I at home and abroad. Therefore, it is of great significance to provide a simple synthesis method of vortioxetine hydrobromide intermediate I. Summary of the invention

[0007] Problem that the invention aims to solve

[0008] In order to solve the above problems existing in the prior art, the present invention provides a method for preparing intermediate I which has short steps, is environmentally friendly, simple and safe to operate, has a high total yield and a mild reaction, has low cost, high economic benefits, is more suitable for industrial production, and has good application prospects.

[0009] Solutions for solving problems

[0010] The present invention provides a method for preparing a vortioxetine hydrobromide intermediate compound I, characterized in that the method comprises the following steps:

[0011]

[0012] Step S2: Compound b is subjected to reduction reaction to obtain compound I.

[0013] Preferably, the step S2 is carried out in the presence of a reducing agent B.

[0014] Preferably, the reducing agent B is selected from one or more of iron / acid, stannous chloride, Pd / C / H2, sodium sulfide and hydrosulfite; preferably iron / acid; preferably one or more of iron / hydrochloric acid, iron / sulfuric acid and iron / acetic acid; preferably iron / acetic acid.

[0015] Preferably, the molar ratio of the compound b to iron is 1:2-10; preferably 1:3-6; preferably 1:4.

[0016] Preferably, the method further comprises the steps of:

[0017]

[0018] Wherein, X is selected from halogen, preferably from F, Cl, Br;

[0019] Step S1: Compound a1 and compound a2 undergo substitution reaction to obtain compound b.

[0020] Preferably, the step S1 is carried out in the presence of a base.

[0021] Preferably, the base is selected from one or more of potassium carbonate, sodium bicarbonate, sodium carbonate, potassium bicarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and calcium oxide, preferably cesium carbonate.

[0022] Preferably, step S1 is performed under lighting conditions.

[0023] Preferably, the lighting condition is 500W natural white light.

[0024] Preferably, the illumination time in step S1 is 10-50 hours, preferably 17-42 hours.

[0025] Preferably, the step S1 is carried out in a solvent.

[0026] Preferably, the solvent is selected from one or more of DMSO, chloroform, acetonitrile and acetone, preferably DMSO.

[0027] Preferably, the step S1 is carried out under the protection of N2.

[0028] Preferably, in step S1, the molar ratio of compound a1 to compound a2 is 1:0.8-1.2, preferably 1:1.

[0029] Effects of the Invention

[0030] The present invention provides a method for preparing a compound shown in formula I, which has a simple synthetic route, cheap and readily available raw materials, simple operation, mild reaction conditions, high product purity and high yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 For intermediate compound b 1 H NMR spectrum.

[0032] Figure 2 For intermediate compound I 1 H NMR spectrum. DETAILED DESCRIPTION

[0033] In order to make the technical solutions and beneficial effects of the present invention more clearly understandable, the following is a detailed description by listing specific embodiments. The drawings are not necessarily drawn to scale, and local features may be enlarged or reduced to more clearly show the details of the local features; unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical field to which this application belongs.

[0034] The present invention provides a method for preparing a vortioxetine hydrobromide intermediate compound I, characterized in that the method comprises the following steps:

[0035]

[0036] Step S2: Compound b is subjected to reduction reaction to obtain compound I.

[0037] In certain embodiments, the step S2 is carried out in the presence of a reducing agent B.

[0038] In certain embodiments, the reducing agent B is selected from one or more of iron / acid, stannous chloride, Pd / C / H2, sodium sulfide and hydrosulfite.

[0039] In certain embodiments, the reducing agent B is selected from iron / acid.

[0040] In certain embodiments, the reducing agent B is selected from one or more of iron / hydrochloric acid, iron / sulfuric acid, and iron / acetic acid.

[0041] In certain embodiments, the reducing agent B is selected from iron / acetic acid.

[0042] In certain embodiments, the molar ratio of compound b to iron is 1:2-10.

[0043] In certain embodiments, the molar ratio of compound b to iron is 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10.

[0044] In certain embodiments, the reaction temperature of step S2 is 10-50°C.

[0045] In certain embodiments, the reaction temperature of step S2 is 10-30°C.

[0046] In certain embodiments, the reaction temperature of step S2 is room temperature.

[0047] In certain embodiments, the reaction time of step S2 is 2-15 h.

[0048] In certain embodiments, the reaction time of step S2 is 5-10 h.

[0049] In certain embodiments, the reaction time of step S2 is 8 hours.

[0050] In certain embodiments, the post-treatment step of step S2 comprises adding ethyl acetate and water after the reaction is completed, separating the liquids, washing the organic phase with water until it is neutral, drying over anhydrous sodium sulfate, filtering, distilling off the organic solvent under reduced pressure, and purifying by column chromatography to obtain intermediate I.

[0051] In certain embodiments, the method further comprises the steps of:

[0052]

[0053] wherein X is selected from halogen,

[0054] Step S1: Compound a1 and compound a2 undergo substitution reaction to obtain compound b.

[0055] In certain embodiments, X is selected from F, Cl, Br.

[0056] In certain embodiments, step S1 is performed in the presence of a base.

[0057] In certain embodiments, the base is selected from one or more of potassium carbonate, sodium bicarbonate, sodium carbonate, potassium bicarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and calcium oxide.

[0058] In certain embodiments, the base is selected from one or more of potassium carbonate, sodium carbonate, and cesium carbonate.

[0059] In certain embodiments, the base is selected from cesium carbonate.

[0060] In certain embodiments, step S1 is performed under light conditions.

[0061] In certain embodiments, the lighting condition is 500W natural white light irradiation.

[0062] In certain embodiments, the illumination time in step S1 is 10-50 hours.

[0063] In certain embodiments, the illumination time in step S1 is 17-42 hours.

[0064] In certain embodiments, step S1 is performed in a solvent.

[0065] In certain embodiments, the solvent is selected from one or more of DMSO, chloroform, acetonitrile, and acetone.

[0066] In certain embodiments, the solvent is selected from DMSO.

[0067] In certain embodiments, the step S1 is carried out under N2 protection.

[0068] In certain embodiments, the molar ratio of compound a1 to compound a2 in step S1 is 1:0.8-1.2.

[0069] In certain embodiments, the molar ratio of compound a1 to compound a2 in step S1 is 1:0.8, 1:0.9, 1:1.0, 1:1.1, or 1:1.2.

[0070] In certain embodiments, the reaction temperature of step S1 is 10-50°C.

[0071] In certain embodiments, the reaction temperature of step S1 is 10-30°C.

[0072] In certain embodiments, the reaction temperature of step S1 is room temperature.

[0073] In certain embodiments, the post-treatment step of step S1 includes removing the light source after the reaction is completed, pouring the reaction solution into an appropriate amount of saturated brine, adding ethyl acetate and stirring, separating the liquids, extracting the aqueous phase twice with ethyl acetate, combining the organic phases, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, evaporating the organic solvent under reduced pressure, and purifying by column chromatography to obtain intermediate b.

[0074] The method of the present invention is described below by means of specific examples. It should be understood that these examples are used to illustrate the basic principles, main features and advantages of the present invention, and the present invention is not limited to the scope of the following examples; the implementation conditions adopted in the examples can be further adjusted according to specific requirements, and the implementation conditions not specified are usually the conditions in routine experiments.

[0075] In the following embodiments 1 H NMR spectra were measured using a Bruker instrument (400 MHz), and chemical shifts were expressed in ppm using tetramethylsilane as an internal standard (0.00 ppm). 1H NMR notation: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, dd = doublet of a doublet, dt = doublet of a triplet. Coupling constants, when given, are given in Hz.

[0076] TLC: Thin layer chromatography. The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.2mm-0.3mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm-0.5mm.

[0077] Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0078] In the following examples, unless otherwise specified, all temperatures are in degrees Celsius. Unless otherwise specified, various starting materials and reagents are commercially available or synthesized according to known methods. Commercially available materials and reagents are used directly without further purification. Unless otherwise specified, commercial manufacturers include but are not limited to Sinopharm Group, J&K Technology Co., Ltd., TCI (Shanghai) Chemical Industry Development Co., Ltd., Shanghai Bid Pharmaceutical Technology Co., Ltd. and Shanghai Myrel Chemical Technology Co., Ltd.

[0079] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0080] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0081] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), and the developing solvent used in the reaction, the system of eluent for column chromatography or the developing solvent system for thin layer chromatography used for purifying the compound includes: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: n-hexane: ethyl acetate; wherein the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagent, such as acetic acid or triethylamine, can also be added for adjustment.

[0082] Example 1

[0083]

[0084] Place 250mL DMSO in a 500mL reaction bottle, add 10g (63.5mmol, 1eq) of m-chloronitrobenzene, 31g (95.2mmol, 1.5eq) of cesium carbonate, and 8.8g (63.5mmol, 1eq) of 2,4-dimethylthiophenol, replace nitrogen, and use 500W natural white light under nitrogen protection to carry out light irradiation reaction for 24h. Remove the light source, pour the reaction solution into 750mL saturated brine, add 250mL ethyl acetate and stir for 15min, separate the liquids, extract the aqueous phase with 250mL ethyl acetate twice, combine the organic phases, wash with saturated brine until neutral, dry with anhydrous sodium sulfate, evaporate to dryness, and purify by column chromatography (eluent PE) to obtain 10.8g of light yellow solid with a purity of 98.1% and a yield of 66%.

[0085] 1 H NMR(400MHz,Chloroform-d)δ7.95–7.90(m,1H),7.85(t,J=2.0Hz,1H),7.43–7.28 (m,3H),7.18(d,J=2.0Hz,1H),7.07(dd,J=7.9,2.0Hz,1H),2.36(d,J=14.7Hz,6H).

[0086] ESI-MS: [M+NH4] + Calculate for C 14 H 17 N2O2S, 277.4; found 277.4.

[0087] Example 2

[0088]

[0089] Place 250 mL of DMSO in a 500 mL reaction bottle, add 10 g (70.9 mmol, 1 eq) of m-fluoronitrobenzene, 34.6 g (106.3 mmol, 1.5 eq) of cesium carbonate, and 9.8 g (70.9 mmol, 1 eq) of 2,4-dimethylthiophenol, replace nitrogen, and use 500 W of natural white light under nitrogen protection to carry out light irradiation reaction for 42 hours. Remove the light source, pour the reaction solution into 750 mL of saturated saline, add 250 mL of ethyl acetate and stir for 15 minutes, separate the liquids, extract the aqueous phase with 250 mL of ethyl acetate twice, combine the organic phases, wash with saturated saline until neutral, dry with anhydrous sodium sulfate, evaporate to dryness, and purify by column chromatography to obtain 9.7 g of light yellow solid with a purity of 97.8% and a yield of 53%.

[0090] Example 3

[0091]

[0092] Place 250mL DMSO in a 500mL reaction bottle, add 10g (49.5mmol, 1eq) of m-bromonitrobenzene, 24.2g (74.2mmol, 1.5eq) of cesium carbonate, and 6.8g (49.5mmol, 1eq) of 2,4-dimethylthiophenol, replace nitrogen, and use 500W natural white light under nitrogen protection to carry out light irradiation reaction for 17h. Remove the light source, pour the reaction solution into 750mL saturated saline, add 250mL ethyl acetate and stir for 15min, separate the liquids, extract the aqueous phase with 250mL ethyl acetate twice, combine the organic phases, wash with saturated saline until neutral, dry with anhydrous sodium sulfate, evaporate to dryness, and purify by column chromatography to obtain 9.1g of light yellow solid with a purity of 98.3% and a yield of 71%.

[0093] Example 4

[0094]

[0095] In a 250 mL reaction bottle, 100 mL of acetic acid and 10 g of nitrosulfide were added respectively, and 8.6 g of reduced iron powder was added in batches. After reacting for 8 h, ethyl acetate and water were added to separate the mixture. The organic phase was washed with water until neutral, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography (eluent: PE~PE:EA=10:1) to obtain 8.8 g of a light yellow oil with a purity of 99.1% and a yield of 99%.

[0096] 1 H NMR(400MHz,Chloroform-d)δ7.32(d,J=7.8Hz,1H),7.10(d,J=2.0Hz,1H),7.05–6.97(m ,2H),6.54(dt,J=7.9,1.2Hz,1H),6.49–6.41(m,2H),3.60(s,2H),2.35(d,J=6.9Hz,6H).

[0097] ESI-MS: [M+H] + Calculate for C 14 H 16 NS, 230.34; found 230.4.

[0098] Comparative Example 1

[0099] Place 250mL of toluene in a 500mL reaction bottle, add 10g (63.5mmol, 1eq) of m-chloronitrobenzene, 31g (95.2mmol, 1.5eq) of cesium carbonate, and 8.8g (63.5mmol, 1eq) of 2,4-dimethylthiophenol, replace nitrogen, and use 500W natural white light under nitrogen protection to carry out light irradiation reaction for 24h. Remove the light source, pour the reaction solution into 750mL of saturated brine, add 250mL of ethyl acetate and stir for 15min, separate the liquids, extract the aqueous phase with 250mL of ethyl acetate twice, combine the organic phases, wash with saturated brine until neutral, dry with anhydrous sodium sulfate, evaporate to dryness, and purify by column chromatography (eluent PE). 2.9g of light yellow solid is obtained, with a yield of 16%.

[0100] Comparative Example 2

[0101] 250 mL of DMF was placed in a 500 mL reaction bottle, and 10 g (63.5 mmol, 1 eq) of m-chloronitrobenzene, 31 g (95.2 mmol, 1.5 eq) of cesium carbonate, and 8.8 g (63.5 mmol, 1 eq) of 2,4-dimethylthiophenol were added. The nitrogen was replaced, and the temperature was raised to 80°C under nitrogen protection for 12 h. The reaction progress was monitored by HPLC, and no reaction occurred.

[0102] Comparative Example 3

[0103] Place 100 mL of toluene in a 250 mL reaction bottle, add Pd(dba)2 (0.16 g, 0.29 mmol) and BINAP (0.36 g, 0.58 mmol) and stir at room temperature for 15 min. Add 10 g (63.5 mmol, 1 eq) of m-chloronitrobenzene, 10.4 g (76.9 mmol, 1.1 eq) of sodium tert-butoxide, and 8.8 g (63.5 mmol, 1 eq) of 2,4-dimethylthiophenol, replace nitrogen, and heat to 110 ° C under nitrogen protection, and reflux for 8 h. Liquid phase detection of the reaction progress showed that no target compound was produced.

[0104] Comparative Example 4

[0105] In a 250 mL reaction bottle, 100 mL of pure water and 10 g of nitrosulfide were added respectively, and 8.6 g of reduced iron powder was added in batches. The reaction progress was monitored by TLC, and no reaction was observed.

[0106] It should be understood that the above embodiments are exemplary and are not intended to include all possible implementations included in the claims. Various modifications and changes may be made on the basis of the above embodiments without departing from the scope of the present disclosure. Similarly, the various technical features of the above embodiments may be arbitrarily combined to form other embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only express several implementations of the present invention and do not limit the scope of protection of the patent of the present invention.

Claims

1. A method for preparing a vortioxetine hydrobromide intermediate compound I, characterized in that: The method comprises the following steps: Step S2: Compound b is subjected to reduction reaction to obtain compound I.

2. The method for preparing vortioxetine hydrobromide intermediate compound I according to claim 1, characterized in that: The step S2 is to react in the presence of a reducing agent B; Preferably, the reducing agent B is selected from one or more of iron / acid, stannous chloride, Pd / C / H2, sodium sulfide and hydrosulfite; preferably iron / acid; preferably one or more of iron / hydrochloric acid, iron / sulfuric acid and iron / acetic acid; preferably iron / acetic acid.

3. The method for preparing vortioxetine hydrobromide intermediate compound I according to claim 1, characterized in that: The molar ratio of the compound b to iron is 1:2-10; preferably 1:3-6; preferably 1:

4.

4. The method for preparing the vortioxetine hydrobromide intermediate compound I according to any one of claims 1 to 3, characterized in that: The method further comprises the steps of: Wherein, X is selected from halogen, preferably from F, Cl, Br; Step S1: Compound a1 and compound a2 undergo substitution reaction to obtain compound b.

5. The method for preparing vortioxetine hydrobromide intermediate compound I according to claim 4, characterized in that: The step S1 is carried out in the presence of a base; Preferably, the base is selected from one or more of potassium carbonate, sodium bicarbonate, sodium carbonate, potassium bicarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and calcium oxide, preferably cesium carbonate.

6. The method for preparing vortioxetine hydrobromide intermediate compound I according to claim 4 or 5, characterized in that: The step S1 is performed under lighting conditions; Preferably, the lighting condition is 500W natural white light.

7. The method for preparing vortioxetine hydrobromide intermediate compound I according to claim 6, characterized in that: The illumination time in step S1 is 10-50 hours, preferably 17-42 hours.

8. The method for preparing vortioxetine hydrobromide intermediate compound I according to claim 4, characterized in that: The step S1 is carried out in a solvent; Preferably, the solvent is selected from one or more of DMSO, chloroform, acetonitrile and acetone, preferably DMSO.

9. The method for preparing vortioxetine hydrobromide intermediate compound I according to claim 4, characterized in that: The step S1 is a reaction carried out under the protection of N2.

10. The method for preparing vortioxetine hydrobromide intermediate compound I according to claim 4, characterized in that: In step S1, the molar ratio of compound a1 to compound a2 is 1:0.8-1.2, preferably 1:1.

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