CN111187264A - Preparation method of mirtazapine and intermediate product thereof - Google Patents
Preparation method of mirtazapine and intermediate product thereof Download PDFInfo
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- CN111187264A CN111187264A CN201811352123.6A CN201811352123A CN111187264A CN 111187264 A CN111187264 A CN 111187264A CN 201811352123 A CN201811352123 A CN 201811352123A CN 111187264 A CN111187264 A CN 111187264A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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Abstract
The invention discloses a preparation method of mirtazapine and an intermediate product thereof, wherein the preparation method of the mirtazapine comprises the following steps: in an organic solvent, carrying out cyclization reaction on a compound shown as a formula I and/or an inorganic acid salt thereof in the presence of sulfonic acid resin, and separating to obtain a solid, namely a mirtazapine intermediate product; and carrying out ion exchange reaction on the intermediate product of the mirtazapine and a base to prepare the mirtazapine. The preparation method has the advantages of simple and convenient operation, easy product separation, small pollution, suitability for industrial production and the like.
Description
Technical Field
The invention relates to a preparation method of mirtazapine and an intermediate product thereof.
Background
Mirtazapine has the following structure, is called Remeron (Remeron), is a noradrenergic and specific 5-HT antidepressant developed by Oganon (N.V. organon) of the Netherlands, has a unique dual action mechanism, and has good clinical curative effect on various types of depression.
There are three main ways of mirtazapine synthesis. WO2001042239 discloses that mandelic acid is used as initial raw material, and the intermediate 2-phenyl-4-methylpiperazine is prepared through 7 steps of esterification, chlorination, aminolysis, amino protection, reduction, methylation, hydrogenation debenzylation and the like, and then the intermediate is condensed with 2-chloro-3-cyanopyridine, hydrolyzed and reduced to obtain 1- (3-hydroxymethyl pyridine-2-yl) -2-phenyl-4-methylpiperazine. US6495685 discloses the direct condensation of phenyl oxirane and N-methyl-2-ethanolamine as starting materials with 2-amino-3-hydroxymethylpyridine to give 1- (3-hydroxymethylpyridin-2-yl) -2-phenyl-4-methylpiperazine. WO20020238552 uses ethyl benzoylformate as a raw material, and reduces with 2-phenyl-4-methylpiperazine-5-one obtained by cyclization of N-methylethylenediamine to obtain 2-phenyl-4-methylpiperazine, and then condenses, hydrolyzes and reduces with 2-chloro-3-cyanopyridine to obtain 1- (3-hydroxymethylpyridine-2-yl) -2-phenyl-4-methylpiperazine.
All of the above routes produce an intermediate of 1- (3-hydroxymethylpyridin-2-yl) -2-phenyl-4-methylpiperazine which is cyclized by dehydration with concentrated sulfuric acid to mirtazapine. These methods all use a large amount of sulfuric acid as a reaction solvent and a catalyst, and are difficult to operate, and reagents such as sulfuric acid cannot be recycled in organic synthesis, and a large amount of acidic waste liquid needs to be treated, so that the method has the defects of large environmental pollution and the like. Therefore, a preparation method of mirtazapine, which is simple to operate, easy to separate the product, low in pollution and suitable for industrial production, is urgently needed to be found.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a preparation method of mirtazapine, which has the advantages of simple and convenient operation, easy product separation, small pollution, suitability for industrial production and the like.
The invention provides a preparation method of a mirtazapine intermediate, which comprises the following steps: in an organic solvent, carrying out cyclization reaction on a compound shown as a formula I and/or an inorganic acid salt thereof in the presence of sulfonic acid resin, and separating the obtained solid to obtain the mirtazapine intermediate product;
in the preparation method of the mirtazapine intermediate product, the compound shown in the formula I and/or the inorganic acid salt thereof is preferably the inorganic acid salt (such as hydrochloride and/or sulfate, and further such as hydrochloride) of the compound shown in the formula I.
In the preparation method of the mirtazapine intermediate, the sulfonic acid resin can be styrene sulfonic acid resin and/or perfluorinated sulfonic acid resin. The styrene sulfonic acid resin can be polystyrene sulfonic acid resin, such as macroporous strong acid polystyrene sulfonic acid resin. The polystyrene sulfonic acid resin can be a success292-1 type resin of Jiangsu Coleisi resin Co. The perfluorinated sulfonic acid resin can be nafion-H type sulfonic acid resin of south China synthetic chemistry, Inc. in Jiangyun city.
In the preparation method of the mirtazapine intermediate, the amount of the sulfonic acid resin can be the conventional amount in the reaction in the field, and for example, the mass ratio of the sulfonic acid resin to the compound shown in the formula I and/or the inorganic acid salt thereof can be 1: 10-2: 1 (for example, 1: 10-3: 10, and further 1: 10-1: 6). Particularly, when the compound shown in the formula I and/or the inorganic acid salt thereof is the inorganic acid salt of the compound shown in the formula I, the mass ratio of the sulfonic acid resin to the inorganic acid salt of the compound shown in the formula I can be 1: 10-3: 10 (for example, 1: 10-1: 6).
In the preparation method of the intermediate product of mirtazapine, the organic solvent can be a conventional solvent in the reaction in the field, such as an aprotic organic solvent. The aprotic organic solvent may be one or more of a chlorinated hydrocarbon solvent (such as dichloromethane and/or trichloromethane, further such as trichloromethane), an ether solvent (such as ethylene glycol dimethyl ether), an aromatic hydrocarbon solvent (such as toluene and/or xylene, further such as toluene) and a halogenated aromatic hydrocarbon solvent (such as chlorobenzene). In some embodiments of the invention, the organic solvent is one or more of ethylene glycol dimethyl ether, toluene, and chloroform.
In the preparation method of the mirtazapine intermediate, the amount of the organic solvent can be the conventional amount in the reaction in the field, for example, the volume-to-mass ratio of the organic solvent to the compound shown in the formula I and/or the inorganic acid salt thereof can be 5-100mL/g (for example, 5-10 mL/g).
In the process for the preparation of mirtazapine intermediate, the reaction temperature of the ring closure reaction may be as conventional in the art, such as 10 ℃ to 110 ℃ (e.g. 60 ℃ to 110 ℃).
Preferably, the cyclization reaction is carried out in an inert gas atmosphere. The inert gas may be one or more of inert gases conventionally used in the art, such as nitrogen, helium, neon, argon, krypton, and radon.
The progress of the cyclization reaction can be monitored by conventional testing methods in the art (e.g., TLC, HPLC, GC or NMR, preferably TLC), and is generally determined as the end point of the reaction when the compound of formula I is no longer reacted.
In the preparation of the intermediate mirtazapine, the separation may be a solid-liquid separation method as is conventional in the art, such as filtration.
The invention also provides a mirtazapine intermediate product prepared by the preparation method of the mirtazapine intermediate product.
The invention also provides a preparation method of mirtazapine, which comprises the following steps:
(1) preparing a mirtazapine intermediate according to the preparation method of the mirtazapine intermediate as described above;
(2) and (2) carrying out ion exchange reaction on the intermediate product of the mirtazapine prepared in the step (1) and a base to obtain the mirtazapine.
In the process for the preparation of mirtazapine, the base in step (2) may be a base conventional in the art such as an organic base (e.g. a water soluble organic base, further e.g. DMAP) and/or an inorganic base (e.g. sodium carbonate, sodium bicarbonate and/or sodium hydroxide). In some embodiments of the invention, the base may be an inorganic base, such as sodium bicarbonate. The alkali can be an aqueous solution of alkali. The operation of the ion exchange reaction may be: and mixing the mirtazapine intermediate with the aqueous solution of the base.
The reaction solvent for the ion exchange reaction may be a solvent conventional in such reactions in the art, such as water. The reaction solvent may be used in an amount conventional in such reactions in the art, for example, the volume to mass ratio of the reaction solvent to the mirtazapine intermediate may be 5-100mL/g (e.g., 5-20 mL/g).
The reaction temperature of the ion exchange reaction may be a reaction temperature conventional in the art, for example, 10 to 90 ℃ (e.g., 10 to 30 ℃).
The ion exchange reaction is generally terminated with the average free nitrogen.
The ion exchange reaction can further comprise the following post-treatment steps after the ion exchange reaction is finished: filtering, washing residual solid by using an organic solvent, extracting by using an aqueous phase, combining organic phases, and concentrating to obtain a mirtazapine crude product. In the post-treatment step, the organic solvent may be an organic solvent conventionally used in the art for extraction, such as an ester solvent (e.g., ethyl acetate).
The preparation method of mirtazapine can further comprise the following purification steps: and recrystallizing the crude mirtazapine to obtain purified mirtazapine. The recrystallization can be carried out by methods conventional in the art for such procedures. The solvent used for recrystallization can be a mixed solvent of (an alcohol solvent and/or a ketone solvent) and water. Wherein the alcohol solvent can be water-soluble alcohol solvent, such as methanol and/or ethanol; the ketone solvent may be a water soluble ketone solvent, such as acetone. In some embodiments of the present invention, the solvent used for recrystallization is a mixed solvent of methanol and water.
In the present invention, the term "sulfonic acid resin" refers to a resin having a sulfonic acid group as a functional group, such as a polystyrenesulfonic acid resin, a perfluorosulfonic acid resin, and the like. "styrene sulfonic acid resin" refers to various sulfonic acid resins having styrene as a main skeleton, and includes polystyrene sulfonic acid resins, polystyrene-divinylbenzene sulfonic acid resins, and halogenated polystyrene sulfonic acid resins (see New polystyrene sulfonic acid resins with enhanced acid and basic properties, Journal of Molecular Catalysis A: Chemical, No. 279, No. 1, No. 2, 2008, pages 63-68), and the like. The sulfonic acid resin can be recycled after regeneration.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: provides a preparation method of mirtazapine, which has the advantages of simple and convenient operation, easy product separation, small pollution, suitability for industrial production and the like.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1
60g of 1- (3-hydroxymethylpyridin-2-yl) -2-phenyl-4-methylpiperazine (compound shown in formula I) is dissolved in acetone, 15mL of 12% hydrochloric acid aqueous solution is added, a large amount of white precipitate is separated out, and vacuum drying is carried out to obtain 50g of 1- (3-hydroxymethylpyridin-2-yl) -2-phenyl-4-methylpiperazine hydrochloride.
Under the protection of nitrogen, 1- (3-hydroxymethylpyridin-2-yl) -2-phenyl-4-methylpiperazine hydrochloride (21.5g) is added into ethylene glycol dimethyl ether (150mL) in batches, 4g of a commercially available polystyrene sulfonic acid resin (ion exchange resin (IONRESIN) supercess 292-1, the temperature is controlled to be not more than 65 ℃, then the mixture is stirred at 60-70 ℃ for 7h, cooled to 10 ℃, filtered to obtain a solid mirtazapine intermediate product of about 25g, the obtained solid is added into a saturated sodium bicarbonate aqueous solution (250mL), stirred at 10-20 ℃ for 1 h, filtered, the residual solid is washed with ethyl acetate (60mL), the filtered solution is extracted with ethyl acetate (120mL) for three times, an organic layer is separated, the organic layers are combined, the solid is obtained by concentration and drying under reduced pressure, the obtained solid is dissolved in methanol (30mL), water (60mL) is added into the solution dropwise at 50-60 ℃, and the solution is cooled to 10-15 ℃ after dropwise addition and stirred for 3 h. Filtered and dried in vacuum to obtain a pure mirtazapine product (13.1 g). Purity 98.5% (normalization method) (HPLC: chromatographic column: Kromasil 100-5C18 — 250 × 4.6mm, detection wavelength: 220nm, flow rate: 1.0mL/min, column temperature: 30 ℃; sample injection amount: 2 μ l, mobile phase: acetonitrile/water: 3/7, ratio is volume ratio), LC-MS [ M + H ]: 266.2.
HNMR(400MHz,CD3OD):δ8.03～8.05(t,1H),7.39(s,1H),7.06～7.18(m，4H),6.75～6.78(m，1H),4.92～4.93(d,1H),4.45～4.48(m,1H),4.22～4.24(d,1H)，3.62～3.60(m,1H),3.32～3.33(m,2H),2.96(br,1H),2.81(br,1H),2.45～2.47(d,1H),2.40(s，3H),2.30～2.33(m,1H).
Example 2
1- (3-Hydroxymethylpyridin-2-yl) -2-phenyl-4-methylpiperazine (26.5g) was added in portions to toluene (180mL) under nitrogen, 53g of a sulfonic acid resin was added, the temperature was controlled not to exceed 65 ℃, and then stirring was carried out at 60-70 ℃ for 7 h. Cooled to 10 ℃ and filtered to obtain 31g of a solid. The obtained solid was added to a saturated aqueous sodium bicarbonate solution (280mL), stirred at 10-20 ℃ for 1 hour, filtered, the residual solid was washed with ethyl acetate (60mL), and the filtered solution was extracted with ethyl acetate (120mL) three times. The organic layer was separated. Mixing the organic phases, concentrating under reduced pressure, and drying to obtain solid; the resulting solid was dissolved in methanol (30mL), water (60mL) was added dropwise to the solution at 50-60 deg.C, and the solution was cooled to 10-15 deg.C and stirred for 3h after dropping. Filtered and dried in vacuum to obtain a pure mirtazapine product (16.1g, purity 99.0%, HPLC assay conditions as in example 1).
Example 3
Under the protection of nitrogen, 1- (3-hydroxymethylpyridin-2-yl) -2-phenyl-4-methylpiperazine hydrochloride (11.5g) was added in portions to toluene (70mL), 1.2g of a commercially available perfluorosulfonic acid resin (nafion-H, a product of south university synthetic chemistry, ltd., jiangyin) was added, the temperature was controlled not to exceed 110 ℃, and then the mixture was stirred at 90 to 110 ℃ for 5 hours. Cooled to 10 ℃ and filtered to give a solid (i.e. mirtazapine intermediate) 14.5 g. The obtained solid was added to a saturated aqueous sodium bicarbonate solution (120mL), stirred at 10-20 ℃ for 1 hour, filtered, the residual solid was washed with ethyl acetate (30mL), and the filtered solution was extracted with ethyl acetate (60mL) three times. The organic layer was separated. Mixing the organic phases, concentrating under reduced pressure, and drying to obtain solid; the resulting solid was dissolved in methanol (30mL), water (60mL) was added dropwise to the solution at 50-60 deg.C, and the solution was cooled to 10-15 deg.C and stirred for 3h after dropping. Filtered and dried in vacuum to obtain a pure mirtazapine product (6.1g, purity 98.5%, HPLC assay conditions as in example 1).
Example 4
Under nitrogen, 1- (3-hydroxymethylpyridin-2-yl) -2-phenyl-4-methylpiperazine hydrochloride (11.5g) was added in portions to chloroform (70mL), 1.2g of a commercially available polystyrenesulfonic acid resin (iorreisin model 292-1) was added, the temperature was controlled to reflux of chloroform, and then stirred under reflux for 7 hours. Cooled and filtered to give a solid (i.e., mirtazapine intermediate) of about 15 g. The obtained solid was added to a saturated aqueous sodium bicarbonate solution (250mL) at 10 ℃ or lower, stirred at 10-20 ℃ for 1 hour, filtered, the residual solid was washed with ethyl acetate (30mL), and the filtered solution was extracted with ethyl acetate (60mL) three times. Mixing the organic phases, concentrating under reduced pressure, and drying to obtain solid; the resulting solid was dissolved in methanol (30mL), water (60mL) was added dropwise to the solution at 50-60 deg.C, and the solution was cooled to 10-15 deg.C and stirred for 3h after dropping. Filtered and dried in vacuum to obtain a pure mirtazapine product (6.1g, purity 98.2%, HPLC assay conditions as in example 1).
The melting point of the pure mirtazapine product prepared in the embodiments 1-4 of the invention is 115.1-117.2 ℃, and the product meets the national pharmacopoeia standard.
Claims (10)
1. A process for the preparation of an intermediate of mirtazapine, comprising the steps of: in an organic solvent, carrying out cyclization reaction on a compound shown as a formula I and/or an inorganic acid salt thereof in the presence of sulfonic acid resin, and separating the obtained solid to obtain the mirtazapine intermediate product;
2. the method of claim 1, wherein: the compound shown in the formula I and/or the inorganic acid salt thereof is the inorganic acid salt of the compound shown in the formula I;
and/or the sulfonic acid resin is styrene sulfonic acid resin and/or perfluorinated sulfonic acid resin;
and/or the mass ratio of the sulfonic acid resin to the compound shown in the formula I and/or the inorganic acid salt thereof is 1: 10-2: 1;
and/or the organic solvent is an aprotic organic solvent;
and/or the volume-to-mass ratio of the organic solvent to the compound shown in the formula I and/or the inorganic acid salt thereof is 5-100 mL/g;
and/or the reaction temperature of the cyclization reaction is 10-110 ℃;
and/or, the cyclization reaction is carried out in an inert gas atmosphere;
and/or the separation method is a solid-liquid separation method.
3. The method of claim 2, wherein: the inorganic acid salt is hydrochloride and/or sulfate;
and/or, the styrene sulfonic acid resin is polystyrene sulfonic acid resin;
and/or the mass ratio of the sulfonic acid resin to the compound shown in the formula I and/or the inorganic acid salt thereof is 1: 10-3: 10;
and/or the aprotic organic solvent is one or more of a chlorinated hydrocarbon solvent, an ether solvent, an aromatic hydrocarbon solvent and a halogenated aromatic hydrocarbon solvent;
and/or the volume-to-mass ratio of the organic solvent to the compound shown in the formula I and/or the inorganic acid salt thereof is 5-10 mL/g;
and/or the reaction temperature of the cyclization reaction is 60-110 ℃;
and/or the solid-liquid separation method is filtration.
4. The method of claim 3, wherein: the inorganic acid salt is hydrochloride;
and/or the polystyrene sulfonic acid resin is a success292-1 type resin of Jiangsu Coleisi resin Co., Ltd;
and/or the perfluorinated sulfonic acid resin is nafion-H type sulfonic acid resin of south China general synthetic chemistry, Inc. of Jiangyin;
and/or the mass ratio of the sulfonic acid resin to the compound shown in the formula I and/or the inorganic acid salt thereof is 1: 10-1: 6;
and/or the chlorinated hydrocarbon solvent is dichloromethane and/or trichloromethane;
and/or the ether solvent is ethylene glycol dimethyl ether;
and/or the aromatic hydrocarbon solvent is toluene and/or xylene;
and/or the halogenated aromatic hydrocarbon solvent is chlorobenzene.
5. The method of claim 4, wherein: the organic solvent is one or more of ethylene glycol dimethyl ether, toluene and chloroform.
6. An intermediate product of mirtazapine prepared by the process of any one of claims 1-5.
7. A process for the preparation of mirtazapine comprising the steps of:
(1) preparing a mirtazapine intermediate according to the preparation process as described in any one of claims 1-5;
(2) and (2) carrying out ion exchange reaction on the intermediate product of the mirtazapine prepared in the step (1) and a base to obtain the mirtazapine.
8. The method of claim 7, wherein: the alkali in the step (2) is organic alkali and/or inorganic alkali;
and/or, the reaction solvent of the ion exchange reaction is water;
and/or the volume mass ratio of the reaction solvent of the ion exchange reaction to the mirtazapine intermediate product is 5-100 mL/g;
and/or the reaction temperature of the ion exchange reaction is 10-90 ℃;
and/or, the operation of the ion exchange reaction is: mixing the mirtazapine intermediate with the aqueous solution of the base;
and/or, the ion exchange reaction further comprises the following post-treatment steps after the ion exchange reaction is completed: filtering, washing residual solid by using an organic solvent, extracting by using an aqueous phase, combining organic phases, and concentrating to obtain a mirtazapine crude product.
9. The method of claim 8, wherein: the organic base is water-soluble organic base;
and/or the inorganic base is sodium carbonate, sodium bicarbonate and/or sodium hydroxide;
and/or the volume mass ratio of the reaction solvent of the ion exchange reaction to the mirtazapine intermediate product is 5-20 mL/g;
and/or the reaction temperature of the ion exchange reaction is 10-30 ℃;
and/or the preparation method of mirtazapine further comprises the following purification steps: and recrystallizing the crude mirtazapine to obtain purified mirtazapine.
10. The method of claim 9, wherein: the alkali is sodium bicarbonate;
and/or the solvent for recrystallization is a mixed solvent of methanol and water.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113666981A (en) * | 2021-08-27 | 2021-11-19 | 江西百思康瑞药业有限公司 | Synthesis method of dydrogesterone |
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| CN113666981A (en) * | 2021-08-27 | 2021-11-19 | 江西百思康瑞药业有限公司 | Synthesis method of dydrogesterone |
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Application publication date: 20200522 |