Preparation method of mianserin hydrochloride intermediate and derivative thereof

Abstract

The invention relates to a preparation method of a mianserin hydrochloride intermediate and a derivative thereof, belongs to the field of drug intermediates, and particularly relates to a method for reducing carbonyl in a core intermediate into hydroxyl so as to thoroughly solve the quality problem caused by a large number of isomer impurities generated in an original process route for preparing mianserin hydrochloride. According to the preparation process of the intermediate, the obtained product is high in purity, does not need to be further purified and is high in yield; the reaction conditions are mild, the reaction can be completed only at 40 DEG C or below, and the method is more suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention relates to a preparation method of a mianserin hydrochloride intermediate and a derivative thereof, and belongs to the field of pharmaceutical intermediates. Background Art

[0002] Mianserin hydrochloride is a new generation of tetracyclic compounds, which mainly has sedative and antidepressant effects in clinical practice. It was developed by Organon of the Netherlands in 1966, which was merged into Schering-Plough in November 2007, and then into Merck in November 2009.

[0003] This product is not available in the United States. In Japan, Merck authorized Daiichi Sankyo Pharmaceutical Co., Ltd. to produce Mianserin Hydrochloride Tablets, with specifications of 10mg (launched in 1983) and 30mg (launched in 1986). In Switzerland, MephaPharma launched 30mg Mianserin Hydrochloride Tablets. According to the database of the website of the State Food and Drug Administration, Mianserin Hydrochloride Tablets are only produced by Shandong Renhetang Pharmaceutical Co., Ltd., with a specification of 30mg, and the approval number is H20010441, the implementation standard is WS1-(X-426)-2003Z, and it was re-registered on April 10, 2015. This product is included in the British Pharmacopoeia (BP2017) and the European Pharmacopoeia (EP9.0), but not in the Chinese Pharmacopoeia (ChP2015), the United States Pharmacopoeia (USP40) and the Japanese Pharmacopoeia (JPXVI, supplement I).

[0004] Mianserin hydrochloride is chemically known as 1,2,3,4,10,14b-hexahydro-2-methyldibenzo[c,f]pyrazine[1,2-a]

[0005] Azapine hydrochloride, molecular formula is C18H 20 N2·HCl, CAS number: 21535-47-7, structural formula is as follows:

[0006]

[0007] Patent EP1136470B1 discloses a synthesis process of mianserin hydrochloride as shown below: styrene oxide and 2-methylethanolamine are used as starting materials, and mianserin free base is prepared through multi-step reactions. The free base is salified with hydrochloric acid / ethyl acetate to obtain the final product.

[0008]

[0009] This technical solution can obtain the compound of formula I through a one-step reaction, but the selectivity of this step reaction is poor, and 5% to 20% of the isomer Ia is produced, resulting in a low yield, and the isomer is difficult to remove; secondly, the reaction temperature of this step reaction is 130±5°C, which has high requirements on equipment and has certain risks in large-scale production.

[0010] Patent EP0612745B1 discloses a synthesis process of mianserin hydrochloride as shown below: styrene oxide and 2-methylethanolamine are used as starting materials, and mianserin free base is prepared through multi-step reactions. The free base is salified with hydrochloric acid / ethyl acetate to obtain the final product mianserin hydrochloride.

[0011]

[0012] This technical solution can obtain the compound of formula I through a one-step reaction, but the selectivity of this step reaction is poor, 5% to 20% of the isomer Ia is produced, and the isomer is difficult to remove; secondly, the reaction temperature of this step reaction is as high as 130±5°C, which has high requirements on equipment and has certain risks in large-scale production.

[0013] Therefore, compared with the prior art process, the present application aims to provide a preparation process for preparing mianserin hydrochloride intermediates and their derivatives; the materials used in the process are cheap and easily available, the preparation conditions are milder, and the product only obtains a single configuration with a high yield, which is more suitable for industrial production. Summary of the invention

[0014] In view of the shortcomings of the prior art, the present invention provides a method for preparing a mianserin hydrochloride intermediate and a derivative thereof. The method is simple to operate, has high purity and high yield of the obtained product, has mild reaction conditions, and is more suitable for large-scale industrial production.

[0015] The present application provides a method for preparing a mianserin hydrochloride intermediate and its derivatives, comprising the following steps:

[0016] Reduction of the carbonyl group in intermediate II or intermediate III to a hydroxyl group

[0017]

[0018] in,

[0019] R1 is selected from C1-C8 alkyl or benzyl, preferably methyl or benzyl;

[0020] X is selected from halogen.

[0021] Specifically, some embodiments of the present application include the following steps: subjecting the intermediate II to a reduction reaction in a first solvent under the action of a reducing agent to obtain an intermediate I,

[0022]

[0023] Wherein, R1 is selected from C1-C8 alkyl or benzyl.

[0024] In some embodiments, the reducing agent is sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium borohydride, or hydrogen;

[0025] In some more preferred embodiments, the reducing agent is sodium borohydride.

[0026] In some embodiments, the first solvent is dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, isopropyl acetate, tetrahydrofuran, or methyl-tetrahydrofuran;

[0027] In some more preferred embodiments, the first solvent is methanol or dichloromethane.

[0028] In some embodiments, the molar ratio of the intermediate II to the reducing agent is 1:(1-5);

[0029] In some more preferred embodiments, the molar ratio of the intermediate II to the reducing agent is 1:

[0030] (1-2).

[0031] In some embodiments, the reaction temperature of the reduction reaction is 0 to 60°C;

[0032] In some more preferred embodiments, the reaction temperature of the reduction reaction is 10-40°C.

[0033] In some embodiments, the method for preparing the mianserin hydrochloride intermediate and its derivatives further comprises the following steps:

[0034] The intermediate III and the intermediate IV react in the second solvent under the action of an acid-binding agent to obtain the intermediate II.

[0035]

[0036] Wherein, R1 is selected from C1-C8 alkyl or benzyl, and X is selected from halogen.

[0037] In some embodiments, the X is selected from -Cl, -Br, or -I.

[0038] In some embodiments, the acid binding agent is selected from N,N-diisopropylethylamine, triethylamine, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate;

[0039] In some more preferred embodiments, the acid binding agent is selected from N,N-diisopropylethylamine.

[0040] In some embodiments, the second solvent is selected from dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, acetone, methyl tert-butyl ether, isopropyl acetate, tetrahydrofuran;

[0041] In some more preferred embodiments, the second solvent is selected from dichloromethane or ethyl acetate.

[0042] In some more preferred embodiments, the R1 is selected from methyl or benzyl.

[0043] Specifically, some embodiments of the present application include the following steps: subjecting the intermediate III to a reduction reaction in a first solvent under the action of a reducing agent to obtain an intermediate III',

[0044]

[0045] Wherein, X is selected from halogen.

[0046] In some embodiments, the reducing agent is sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium borohydride, or hydrogen;

[0047] In some more preferred embodiments, the reducing agent is sodium borohydride.

[0048] In some embodiments, the first solvent is dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, isopropyl acetate, tetrahydrofuran, or methyl-tetrahydrofuran;

[0049] In some more preferred embodiments, the first solvent is methanol or dichloromethane.

[0050] In some embodiments, the molar ratio of the intermediate III to the reducing agent is 1:(1-5);

[0051] In some more preferred embodiments, the molar ratio of the intermediate III to the reducing agent is 1:(1-2).

[0052] In some embodiments, the reaction temperature of the reduction reaction is 0 to 60°C;

[0053] In some more preferred embodiments, the reaction temperature of the reduction reaction is 10-40°C.

[0054] In some embodiments, the method for preparing the mianserin hydrochloride intermediate and its derivatives further comprises the following steps:

[0055] The intermediate III and the intermediate IV react in the second solvent under the action of an acid-binding agent to obtain the intermediate II.

[0056] The intermediate III' and the intermediate IV react in the second solvent under the action of an acid-binding agent to obtain the intermediate I.

[0057]

[0058] In some embodiments, the acid binding agent is selected from N,N-diisopropylethylamine, triethylamine, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate;

[0059] In some more preferred embodiments, the acid binding agent is selected from N,N-diisopropylethylamine.

[0060] In some embodiments, the second solvent is selected from dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, acetone, methyl tert-butyl ether, isopropyl acetate, tetrahydrofuran;

[0061] In some more preferred embodiments, the second solvent is selected from dichloromethane or ethyl acetate.

[0062] In some embodiments, the X is selected from -Cl, -Br, or -I.

[0063] In some more preferred embodiments, the R1 is selected from methyl or benzyl.

[0064] Due to the adoption of the above technical solution, the present application has the following advantages compared with the prior art:

[0065] The present application provides a method for preparing a mianserin hydrochloride intermediate and its derivatives. The method uses a reducing agent to reduce the carbonyl group in the reaction material III or II to a hydroxyl group, that is, the intermediate I is prepared by II in the present application, or III is first reduced to obtain III' and then the intermediate I is generated. Both of these can completely solve the quality problem caused by the generation of a large amount of isomeric impurities in the original process route for preparing mianserin hydrochloride; through the preparation process of the intermediate I of the present application, the obtained product has high purity, does not require further purification, and has a high yield; the reaction conditions are mild, and the reaction can be completed at only below 40°C, which is more suitable for large-scale industrial production. DETAILED DESCRIPTION

[0066] The present invention is further described in detail below in conjunction with the embodiments, but the present invention is not limited thereto. Any equivalent substitutions in the art made according to the disclosure of the present invention shall fall within the protection scope of the present invention.

[0067] The structures of compounds were determined by mass spectrometry (MS) or nuclear magnetic resonance (NMR). 1 H-NMR).

[0068] Nuclear magnetic resonance (NMR) 1H-NMR) shifts (δ) are given in parts per million (ppm); nuclear magnetic resonance ( 1 H-NMR) was measured using a Bruker AVANCE-400 nuclear magnetic spectrometer, the solvent was deuterated dimethyl sulfoxide (DMSO-d6), the internal standard was tetramethylsilane (TMS), and the chemical shift was 10 -6 (ppm) is given as the unit.

[0069] Mass spectrometry (MS) was performed using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Therm, model: Finnigan LCQ advantage MAX).

[0070] In the following, unless otherwise specified, all raw materials are purchased from outside or prepared by conventional methods in the art.

[0071] Example 1 Preparation of 2-((2-hydroxyethyl)(methyl)amino)-1-phenylethane-1-ol of Formula I

[0072]

[0073] Dissolve 50.0g of the intermediate II in 100ml of methanol, add 12.6g of sodium borohydride at a temperature of 0-40°C, raise the temperature to 30°C for reaction for 5h, and cool to 0°C after the addition. Add hydrochloric acid to quench the reaction, add 200ml of water and 200ml of dichloromethane for stirring, separate the layers, wash the lower organic phase once with 500ml of saturated sodium chloride, collect the organic phase, dry it with anhydrous sodium sulfate, and concentrate it to dryness under reduced pressure at 40°C to obtain 46.58g of 2-((2-hydroxyethyl)(methyl)amino)-1-phenylethane-1-ol as an oil, with a yield of 92.20% and a purity of 98.56%.

[0074] Example 2 Preparation of 2-((2-hydroxyethyl)(methyl)amino)-1-phenylethane-1-ol of Formula I

[0075] Dissolve 50.0g of the intermediate II in 100ml of methanol, add 15.2g of sodium borohydride at a temperature of 0-40°C, raise the temperature to 30°C for reaction for 5h, and cool to 0°C after the addition. Add hydrochloric acid to quench the reaction, add 200ml of water and 200ml of dichloromethane, stir, separate the layers, wash the lower organic phase once with 500ml of saturated sodium chloride, collect the organic phase, dry it with anhydrous sodium sulfate, and concentrate under reduced pressure at 40°C to obtain 45.28g of 2-((2-hydroxyethyl)(methyl)amino)-1-phenylethane-1-ol as an oil, with a yield of 89.6% and a purity of 98.26%.

[0076] Example 3 Preparation of 2-((2-hydroxyethyl)(methyl)amino)-1-phenylethane-1-ol of Formula I

[0077] Dissolve 50.0g of the intermediate II in 100ml of methanol, add 18.3g of sodium borohydride at a temperature of 0-40°C, raise the temperature to 30°C and react for 5h, and cool to 0°C after the reaction is complete. Add hydrochloric acid to quench the reaction, add 200ml of water and 200ml of dichloromethane and stir, separate the layers, wash the lower organic phase once with 500ml of saturated sodium chloride, collect the organic phase, dry it with anhydrous sodium sulfate, and concentrate under reduced pressure at 40°C to obtain 47.36g of 2-((2-hydroxyethyl)(methyl)amino)-1-phenylethane-1-ol as an oil, with a yield of 93.75% and a purity of 98.47%.

[0078] Example 4 Preparation of 2-((2-hydroxyethyl)(methyl)amino)-1-phenylethane-1-ol of Formula I

[0079] Dissolve 50.0g of the intermediate II in 100ml of methanol, add 19.6g of sodium borohydride at a temperature of 0-40°C, raise the temperature to 40°C for reaction for 4h, and cool to 0°C after the addition. Add hydrochloric acid to quench the reaction, add 200ml of water and 200ml of dichloromethane for stirring, separate the layers, wash the lower organic phase once with 500ml of saturated sodium chloride, collect the organic phase, dry it with anhydrous sodium sulfate, and concentrate under reduced pressure at 40°C to obtain an oily substance, 44.28g of 2-((2-hydroxyethyl)(methyl)amino)-1-phenylethane-1-ol, with a yield of 87.65% and a purity of 98.86%.

[0080] Example 5 Preparation of 2-((2-hydroxyethyl)(methyl)amino)-1-phenylethane-1-ol of Formula I

[0081] Dissolve 50.0g of the intermediate II in 100ml of methanol, add 19.6g of sodium borohydride at a temperature of 0-40°C, raise the temperature to 20°C and react for 6h, and cool to 0°C after the reaction is complete. Add hydrochloric acid to quench the reaction, add 200ml of water and 200ml of dichloromethane and stir, separate the layers, wash the lower organic phase once with 500ml of saturated sodium chloride, collect the organic phase, dry it with anhydrous sodium sulfate, and concentrate under reduced pressure at 40°C to obtain 46.35g of 2-((2-hydroxyethyl)(methyl)amino)-1-phenylethane-1-ol as an oil, with a yield of 91.7% and a purity of 98.16%.

[0082] Example 6 Preparation of Formula I 2-((2-hydroxyethyl)(methyl)amino)-1-phenylethane-1-ol

[0083] Dissolve 50.0g of the intermediate II in 100ml of methanol, add 19.6g of sodium borohydride at a temperature of 0-40°C, react at 10°C for 7h, and cool to 0°C after the addition. Add hydrochloric acid to quench the reaction, add 200ml of water and 200ml of dichloromethane, stir, separate into layers, wash the lower organic phase once with 500ml of saturated sodium chloride, collect the organic phase, dry it with anhydrous sodium sulfate, and concentrate under reduced pressure at 40°C to obtain 45.78g of 2-((2-hydroxyethyl)(methyl)amino)-1-phenylethane-1-ol as an oil, with a yield of 90.6% and a purity of 97.99%.

[0084] Example 7 Preparation of Formula I 2-((2-hydroxyethyl)(methyl)amino)-1-phenylethane-1-ol

[0085] Dissolve 50.0g of the intermediate II in 500ml of methanol, add 19.6g of sodium borohydride at a temperature of 0-40°C, react at 30°C for 5h, and cool to 0°C after the addition. Add hydrochloric acid to quench the reaction, add 200ml of water and 200ml of dichloromethane, stir, separate into layers, wash the lower organic phase once with 500ml of saturated sodium chloride, collect the organic phase, dry it with anhydrous sodium sulfate, and concentrate under reduced pressure at 40°C to obtain 43.88g of 2-((2-hydroxyethyl)(methyl)amino)-1-phenylethane-1-ol as an oil, with a yield of 86.9% and a purity of 98.99%.

[0086] Example 8 Preparation of 2-((2-hydroxyethyl)(methyl)amino)-1-phenylethane-1-one represented by formula II

[0087]

[0088] 20.0 g of the compound of formula III was dissolved in 100 ml of dichloromethane, and 10.5 g of N,N-diisopropylethylamine was slowly added dropwise at a temperature of 0-30°C. After the addition was completed, 12.2 g of the compound of formula IV was slowly added dropwise at a temperature of 20-30°C. After the addition was completed, the reaction was kept warm for 12 hours. 100 ml of water was added, and the layers were stirred and separated. The lower organic phase was dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, 50 ml of ethyl acetate was added, and the mixture was heated to reflux for 1 hour. 200 ml of n-heptane was slowly added dropwise, and the mixture was cooled to 0-5°C for crystallization for 2 hours. The mixture was filtered and dried to obtain 20.61 g of 2-((2-hydroxyethyl)(methyl)amino)-1-phenylethane-1-one with a yield of 82.44% and a purity of 99.43%.

[0089] Example 9 Preparation of 2-((2-hydroxyethyl)(methyl)amino)-1-phenylethane-1-one represented by formula II

[0090] 20.0 g of the compound of formula III was dissolved in 100 ml of dichloromethane, and 12.5 g of N,N-diisopropylethylamine was slowly added dropwise at a temperature of 0-30° C. After the addition was completed, 12.2 g of the compound of formula IV was slowly added dropwise at a temperature of 20-30° C. After the addition was completed, the reaction was kept warm for 12 hours, 100 ml of water was added, the layers were stirred and separated, the lower organic phase was dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, 50 ml of ethyl acetate was added, the mixture was heated to reflux for 1 hour, 200 ml of n-heptane was slowly added dropwise, the mixture was cooled to 0-5° C. for crystallization for 2 hours, filtered, and dried to obtain 21.04 g of 2-((2-hydroxyethyl)(methyl)amino)-1-phenylethane-1-one with a yield of 84.16% and a purity of 99.21%.

[0091] Example 10 Preparation of 2-((2-hydroxyethyl)(methyl)amino)-1-phenylethane-1-one represented by formula II

[0092] 20.0 g of the compound of formula III was dissolved in 100 ml of dichloromethane, and 12.5 g of N,N-diisopropylethylamine was slowly added dropwise at a temperature of 0-30°C. After the addition was completed, 13.2 g of the compound of formula IV was slowly added dropwise at a temperature of 20-30°C. After the addition was completed, the reaction was kept warm for 12 hours. 100 ml of water was added, stirred and layered, the lower organic phase was dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, 50 ml of ethyl acetate was added, and the mixture was heated to reflux for 1 hour. 200 ml of n-heptane was slowly added dropwise, and the mixture was cooled to 0-5°C for crystallization for 2 hours. The mixture was filtered and dried to obtain 20.05 g of 2-((2-hydroxyethyl)(methyl)amino)-1-phenylethane-1-one with a yield of 80.2% and a purity of 98.79%.

[0093] Example 11 Preparation of 2-((2-hydroxyethyl)(methyl)amino)-1-phenylethane-1-one represented by formula II

[0094] 20.0 g of the compound of formula III was dissolved in 200 ml of dichloromethane, and 13.5 g of N,N-diisopropylethylamine was slowly added dropwise at a temperature of 0-30°C. After the addition was completed, 13.2 g of the compound of formula IV was slowly added dropwise at a temperature of 20-30°C. After the addition was completed, the reaction was kept warm for 10 hours. 100 ml of water was added, and the layers were stirred and separated. The lower organic phase was dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, 50 ml of ethyl acetate was added, and the mixture was heated to reflux for 1 hour. 200 ml of n-heptane was slowly added dropwise, and the mixture was cooled to 0-5°C for crystallization for 4 hours. The mixture was filtered and dried to obtain 21.05 g of 2-((2-hydroxyethyl)(methyl)amino)-1-phenylethane-1-one with a yield of 84.2% and a purity of 98.66%.

[0095] Example 12 Preparation of Intermediate III'2-Chlorophenylethanol

[0096]

[0097] Dissolve 50.0 g of the compound of formula III in 100 ml of methanol, add 18.5 g of sodium borohydride at a temperature of 0-40°C, react at 30°C for 5 h, and cool to 0°C after the addition. Add hydrochloric acid to quench the reaction, add 200 ml of water and 200 ml of dichloromethane, stir, separate the layers, wash the lower organic phase once with 500 ml of 15% sodium chloride, collect the organic phase, dry it with anhydrous sodium sulfate, and concentrate under reduced pressure at 40°C to obtain 45.36 g of 2-chlorophenylethanol as an oil, with a yield of 89.6% and a purity of 98.88%.

[0098] Example 13 Preparation of Intermediate III'2-Chlorophenylethanol

[0099] Dissolve 50.0 g of the compound of formula III in 200 ml of methanol, add 17.3 g of sodium borohydride at a temperature of 0-40°C, react at 20°C for 5 h, and cool to 0°C after the addition. Add hydrochloric acid to quench the reaction, add 200 ml of water and 200 ml of dichloromethane, stir, separate the layers, wash the lower organic phase once with 500 ml of 15% sodium chloride, collect the organic phase, dry it with anhydrous sodium sulfate, and concentrate under reduced pressure at 40°C to obtain 46.57 g of 2-chlorophenylethanol as an oil, with a yield of 92.1% and a purity of 99.01%.

[0100] Example 14 Preparation of Intermediate III'2-Chlorophenylethanol

[0101] Dissolve 50.0 g of the compound of formula III in 200 ml of methanol, add 16.2 g of sodium borohydride at a temperature of 0-40°C, react at 0°C for 7 h, and cool to 0°C after the addition. Add hydrochloric acid to quench the reaction, add 200 ml of water and 200 ml of dichloromethane, stir, separate into layers, wash the lower organic phase once with 500 ml of 15% sodium chloride, collect the organic phase, dry it with anhydrous sodium sulfate, and concentrate under reduced pressure at 40°C to obtain 44.25 g of 2-chlorophenylethanol as an oil, with a yield of 83.6% and a purity of 98.13%.

[0102] Example 15 Preparation of 2-((2-hydroxyethyl)(methyl)amino)-1-phenylethane-1-ol of Formula I

[0103]

[0104] Dissolve 20.0 g of the compound of formula III' in 100 ml of dichloromethane, add 33.0 g of N,N-diisopropylethylamine, slowly dropwise add 14.26 g of the compound of formula IV, react at 25°C for 12 h, add 100 ml of water, stir and separate the liquids, collect the organic phase, extract the aqueous phase twice with dichloromethane, wash the combined organic phases once with water, collect the organic phases, dry them over anhydrous sodium sulfate, and concentrate under reduced pressure at 40°C to obtain 22.56 g of 2-((2-hydroxyethyl)(methyl)amino)-1-phenylethane-1-ol as an oily substance with a yield of 90.5% and a purity of 98.76%.

[0105] Example 16 Preparation of 2-((2-hydroxyethyl)(methyl)amino)-1-phenylethane-1-ol of Formula I

[0106] 20.0 g of the compound of formula III' was dissolved in 100 ml of dichloromethane, 30.5 g of N,N-diisopropylethylamine was added, and 15.6 g of the compound of formula IV was slowly added dropwise. After the addition was completed, the mixture was reacted at 25°C for 12 h, 100 ml of water was added, and the mixture was stirred for separation. The organic phase was collected, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed once with water, and the collected organic phases were dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure at 40°C to obtain 21.89 g of 2-((2-hydroxyethyl)(methyl)amino)-1-phenylethane-1-ol as an oily substance with a yield of 87.8% and a purity of 98.59%.

[0107] Example 17 Preparation of 2-((2-hydroxyethyl)(methyl)amino)-1-phenylethane-1-ol of Formula I

[0108] 20.0 g of the compound of formula III' was dissolved in 200 ml of dichloromethane, 30.5 g of N,N-diisopropylethylamine was added, and 15.6 g of the compound of formula IV was slowly added dropwise. After the addition was completed, the mixture was reacted at 35°C for 10 h, 100 ml of water was added, and the mixture was stirred for separation. The organic phase was collected, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed once with water. The collected organic phases were dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure at 40°C to obtain 22.79 g of 2-((2-hydroxyethyl)(methyl)amino)-1-phenylethane-1-ol as an oily substance with a yield of 91.4% and a purity of 98.81%.

[0109] Example 18 Preparation of 2-((2-hydroxyethyl)(methyl)amino)-1-phenylethane-1-ol of Formula I

[0110] 20.0 g of the compound of formula III' was dissolved in 200 ml of dichloromethane, 23.26 g of triethylamine was added, and 15.6 g of the compound of formula IV was slowly added dropwise. After the addition was completed, the mixture was reacted at 10°C for 18 h, 100 ml of water was added, and the mixture was stirred for separation. The organic phase was collected, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed once with water, and the collected organic phases were dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure at 40°C to obtain 20.53 g of 2-((2-hydroxyethyl)(methyl)amino)-1-phenylethane-1-ol as an oily substance with a yield of 82.3% and a purity of 97.81%.

[0111] Example 19-21 Reducing agent screening experiment

[0112] Referring to the preparation process of Example 1, Examples 19-21 are different from Example 1 only in the reducing reagents used.

[0113]

[0114] Example 22-25 First solvent screening experiment

[0115] Referring to the preparation process of Example 1, Examples 22-25 are different from Example 1 only in the first solvent used.

[0116] Example Experimental protocol Solvents Yield purity 22 Same as Example 1 Dichloromethane 81.25％ 96.25％ 23 Same as Example 1 Ethanol 82.43％ 97.11％ 24 Same as Example 1 Isopropyl alcohol 82.69％ 97.55％ 25 Same as Example 1 Tetrahydrofuran 81.36％ 96.89％

[0117] Although the present invention is described herein with reference to the illustrative embodiments of the present invention, it should be understood that those skilled in the art can design many other modifications and implementations, which will fall within the scope and spirit of the principles disclosed in the present application. More specifically, within the scope disclosed in the present application, multiple variations and improvements can be made to the components and / or layout of the subject combination layout. In addition to the variations and improvements made to the components and / or layout, other uses will also be apparent to those skilled in the art.

Claims

1. A Mianserin hydrochloride intermediate and a method for preparing a derivative thereof, characterized in that: The following steps are involved: Reduction of the carbonyl group in intermediate II or intermediate III to a hydroxyl group in, R1 is selected from C1-C8 alkyl or benzyl, preferably methyl or benzyl; X is selected from halogen.

2. The preparation method according to claim 1, characterized in that: The intermediate II undergoes a reduction reaction in the first solvent under the action of a reducing agent to obtain an intermediate I. Wherein, R1 is selected from C1-C8 alkyl or benzyl.

3. The preparation method according to claim 1, characterized in that: The intermediate III undergoes a reduction reaction in the first solvent under the action of a reducing agent to obtain an intermediate III ， , Wherein, X is selected from halogen.

4. The preparation method according to any one of claims 1 to 3, characterized in that The reducing agent is sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium borohydride or hydrogen; preferably sodium borohydride.

5. The preparation method according to any one of claims 1 to 3, characterized in that: The first solvent is dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, isopropyl acetate, tetrahydrofuran or methyl- Tetrahydrofuran; preferably methanol or dichloromethane.

6. The preparation method according to claim 4, characterized in that: The molar ratio of the intermediate II or intermediate III to the reducing agent is 1:(1-5), preferably 1:(1-2).

7. The preparation method according to any one of claims 1 to 3, characterized in that: The reaction temperature of the reduction reaction is 0 to 60°C, preferably 10 to 40°C.

8. The preparation method according to claim 2, characterized in that: The preparation method further comprises the following steps: intermediate formula III and intermediate formula IV react in a second solvent under the action of an acid-binding agent to obtain intermediate formula II, The acid binding agent is selected from N,N-diisopropylethylamine, triethylamine, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate; preferably N,N-diisopropylethylamine; The second solvent is dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, acetone, methyl tert-butyl ether, isopropyl acetate, tetrahydrofuran; preferably dichloromethane or ethyl acetate.

9. The preparation method according to claim 3, characterized in that: The preparation method further comprises the following steps: the intermediate of formula III ， and the intermediate IV in the presence of an acid-binding agent in a second solvent to obtain the intermediate I, The acid binding agent is selected from N,N-diisopropylethylamine, triethylamine, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate; preferably N,N-diisopropylethylamine; The second solvent is dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, acetone, methyl tert-butyl ether, isopropyl acetate, tetrahydrofuran; preferably dichloromethane or ethyl acetate.

10. The preparation method according to any one of claims 1, 3, 8 or 9, characterized in that: The X is selected from -Cl, -Br or -I.

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