CN110194719B - Preparation method of R- (-) -atomoxetine hydrochloride - Google Patents
Preparation method of R- (-) -atomoxetine hydrochloride Download PDFInfo
- Publication number
- CN110194719B CN110194719B CN201910506272.1A CN201910506272A CN110194719B CN 110194719 B CN110194719 B CN 110194719B CN 201910506272 A CN201910506272 A CN 201910506272A CN 110194719 B CN110194719 B CN 110194719B
- Authority
- CN
- China
- Prior art keywords
- tomoxetine
- mandelate
- phenyl
- reaction
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/06—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton from hydroxy amines by reactions involving the etherification or esterification of hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
- C07C59/48—Unsaturated compounds containing hydroxy or O-metal groups containing six-membered aromatic rings
- C07C59/50—Mandelic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention provides a preparation method of R- (-) -atomoxetine hydrochloride, which comprises the steps of preparing 3-methylamino-1-phenyl-1-propanol by taking 1-phenyl-2-propenyl-1-ketone as a starting raw material, etherifying the 3-methylamino-1-phenyl-1-propanol with o-halotoluene in an inorganic base environment, resolving by L- (+) -mandelic acid to obtain R- (-) -tomoxetine-S- (+) -mandelate, refining the R- (-) -tomoxetine-S- (+) -mandelate, and converting hydrochloride to obtain the R- (-) -atomoxetine hydrochloride. The method saves one step of refining the intermediate oxalate, reduces the reaction steps, has the advantages of cheap and easily obtained raw and auxiliary materials, less side reactions, low toxicity of reaction solvents, high yield, high purity, low cost and the like, and is suitable for industrial production.
Description
Technical Field
The invention relates to the field of medicines, and in particular relates to a preparation method of R- (-) -atomoxetine hydrochloride.
Background
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
Attention Deficit Hyperactivity Disorder (ADHD) is called Hyperactivity Disorder in China, is a common mental Disorder in childhood, is manifested by inattention, short Attention time, Hyperactivity and impulsivity which are not appropriate for age and development level, and is often accompanied by learning difficulty, conduct Disorder and maladaptation. The symptoms mostly occur before the age of 7 years, and continuously affect the cognition, emotion, behavior, life quality and social functions of children patients, and most of the symptoms are affected by other types of behavior or emotional problems/disorders.
Tomoxetine hydrochloride (CAS:82248-59-7), chemical name (-) -N-methyl-3-phenyl-3- (O-oxotoluene) -propylamine hydrochloride, structural formula is shown below.
The drug was developed by Lilly corporation and approved by the Food and Drug Administration (FDA) in 2002, and marketed in the united states in 2003-1 month, is a selective norepinephrine reuptake inhibitor for the treatment of attention deficit disorder (hyperactivity disorder) in children, adolescents, and adult patients, and is the first non-central excitatory drug approved by FDA in this field in the last decade. The action mechanism is to inhibit the reuptake of 5-hydroxytryptamine (5-HT) by nerve cells, increase the concentration of 5-HT in synaptic cleft, and improve the mood of patients. The medicine has strong selectivity and small cholinergic side effect, the curative effect of the medicine is equivalent to that of a tricyclic medicine, and the adverse reaction is obviously less than that of the tricyclic medicine. The ADHD market is currently dominated by stimulants, such as methylphenidate, Ritalin, by Nowa/Celgene. The tomoxetine hydrochloride is used as a selective norepinephrine reuptake inhibitor, provides a first alternative medicine which can replace a psychostimulant and be used at irregular intervals for patients, and has a good market prospect.
The preparation of the tomoxetine hydrochloride mainly comprises two major types of chemical synthesis and microbial synthesis, wherein the chemical synthesis mainly comprises two paths of a racemate resolution method and an asymmetric synthesis method due to a chiral center of the chemical synthesis; the microbial synthesis also comprises the following steps of firstly preparing a chiral center: the N-substituted gamma-chiral amino alcohol is obtained by lipase resolution, whole cell transformation and the like, and then etherification or other chemical reactions are carried out. The microbial catalysis method has the advantages of safety, environmental protection and the like, but related researches are still in basic application research at present, and more problems are yet to be solved in the aspect of large-scale industrialization; the asymmetric synthesis method in the chemical method adopts chiral ligands, so the price is high, and certain defects exist in the aspect of industrialization.
The inventor finds that the current industrialization route of the tomoxetine hydrochloride is mainly a chemical resolution method, a tomoxetine hydrochloride racemate is prepared firstly, and then the tomoxetine hydrochloride racemate is obtained through chiral resolution of L-mandelic acid and the like, and the method mainly comprises the following routes:
route one: U.S. Pat. No.4314081, journal of chinese pharmaceutical chemistry, 2005(15) 5: 282-284
The method comprises the steps of preparing a gamma-bromide by using 3-chloropropane as an initial material and adopting N-bromosuccinimide (NBS) bromination, carrying out etherification reaction with o-phenol, then reacting with a methylamine water solution at 140 ℃ for 12 hours to obtain a tomoxetine hydrochloride racemate, and splitting and salifying to obtain a finished product. However, the amination of the route is a high-temperature and high-pressure reaction, so that the operation safety has a greater risk; at the same time, under the condition of strong alkali, the halide may produce removing reaction to produce side product.
And a second route: U.S. Pat. No.4314081
N, N-dimethylamino propiophenone is used as an initial material, reduction, chlorination, nucleophilic substitution and demethylation are carried out to obtain the tomoxetine racemate, and a finished product is obtained by splitting and salifying. However, the demethylation in the process adopts cyanogen bromide which is a highly toxic substance, and has larger safety risk in operation.
And a third route: WO2015001565
3-chloro-1-phenyl-1-acetone is used as an initial material, 3-chloro-1-phenyl-1-propanol is obtained through reduction, and then the 3-chloro-1-phenyl-1-propanol and methylamine aqueous solution are prepared to obtain the 3-methylamino-1-phenyl-1-propanol, wherein the purity of the product is low (about 85 percent), so that the subsequent purification is difficult, meanwhile, the time required by low-temperature amination is long, and high-pressure reaction is required at high temperature; then etherifying with ortho-phenol or ortho-fluorotoluene, and catalyzing the etherification by using organic base (such as tertiary butanol); in the route, N-dimethylacetamide and N-methylpyrrolidone are used as solvents, and the adopted solvents have high toxicity (N-methylpyrrolidone has certain skin toxicity), are expensive and cause high cost.
And a fourth route: the Chinese journal of pharmacy 2010,45(14):1104-1106. Guangzhou chemical 2015, (22): 51-53.
Cheap acetophenone is used as a raw material and is obtained through Mannich reaction and reduction, but byproducts in the route are more, particularly in the process of preparing 3-methylamino-1-phenyl-1-acetone hydrochloride through the Mannich reaction, a three-stage Mannich base byproduct is easily formed, as shown in the following route, although the three-stage Mannich base byproduct can be converted into methamphetamine through steam distillation, the energy consumption in the process is higher, and the yield is only about 85%.
Three-stage mannich base by-product generation route
In the etherification reaction of the above routes, both the etherification reactions need to be carried out under strong alkaline conditions, and there are two main types reported in the literature, one is the use of strong organic bases, such as potassium tert-butoxide, sodium methoxide and the like; one is to use strong inorganic bases, such as solid NaOH or KOH, etc.
Chinese patent CN201210329697.8 takes (E) -3- (N-methylamino) -1-phenyl-2-propylene-1-ketone as a raw material, and the raw material is reduced and etherified with 2-halogenated toluene to generate the tomoxetine, but the initial material 1-phenyl propynone is searched and found to have no commercial product, the source is not easy to obtain, and the industrialization has certain difficulty; simultaneously adopts Pd-C/H2、Pd(OH)2-C/H2、Raney Ni/H2The catalyst is used for carrying out hydrogen high-pressure reduction on unsaturated double bonds, and high risk exists in safe operation.
U.S. Pat. No.6541668 reports etherification with 1,3 dimethyl-2-imidazolidinone or N-methylpyrrolidone as solvent under the action of organic base, the solvent used has strong toxicity (1,3 dimethyl-2-imidazolidinone has reproductive toxicity, N-methylpyrrolidone has skin toxicity), and the reaction time is long, the number of operation steps is large, and the solvent dosage is large.
University of Zhejiang oceanic university newspaper (Nature science edition), 2017,36 (06): 546-550; proceedings of north river science and technology university, 2008,29 (4): 328-S331 adopts inorganic strong base to carry out heterogeneous reaction with 3-methylamino-1-phenylpropanol, uses aprotic polar solvent DMF as reaction solvent, in order to promote the increase of oxygen anion concentration and increase the exposure degree, adopts PEG-6000 with similar property with crown ether as catalyst, shortens the reaction time, improves the reaction yield, obtains better effect, and the total yield of racemate reaches 75%, but because of high temperature reaction, the adopted solvent DMF or DMAc is easy to have displacement reaction with N-H of methamphetamine phenylpropanol (org. process Res. Dev.2014,18, 875-S885) to generate amide impurities, and the structural formula is shown as follows:
U.S. Pat. No.7317127B2 uses dimethyl sulfoxide as the aprotic polar solvent as the etherification solvent, but DMSO has certain toxicity, has permeability to human skin and irritation to eyes, and the reaction requires long-time high-temperature (145-147 ℃) reaction, DMSO in the reaction kettle can be decomposed at more than 120 ℃, toxic gas is generated, and dizziness and smell are very unpleasant.
Disclosure of Invention
Aiming at various defects in the prior art, the invention provides a preparation method of R- (-) -atomoxetine hydrochloride, which takes cheap and easily-obtained 1-phenyl-2-propenyl-1-ketone as a starting material to perform Aza-Michael reaction with an alcohol solution of methylamine, adds sodium borohydride serving as a reducing agent into a reaction finished solution in batches, prepares 3-methylamino-1-phenyl-1-propanol by a one-pot method, then takes toluene as a water carrying agent in a solvent with low toxicity and high boiling point, etherifies the toluene with o-halotoluene in an inorganic alkali environment, and directly resolves L-mandelic acid (L- (+) -mandelic acid) into salt (R- (-) -tomoxetine-S- (+) -mandelate), Refining and transferring hydrochloride to obtain the finished product of R- (-) -atomoxetine hydrochloride. The method saves one step of refining the intermediate oxalate, reduces the reaction steps, has the advantages of cheap and easily obtained raw and auxiliary materials, less side reactions, low toxicity of reaction solvents, high yield, high purity, low cost and the like, and is suitable for industrial production.
Specifically, the technical scheme of the invention is as follows:
the invention provides a preparation method of R- (-) -atomoxetine hydrochloride, which takes compound 1, namely 1-phenyl-2-propenyl-1-ketone, as an initial raw material to prepare compound 2, namely 3-methylamino-1-phenyl-1-propanol, and etherifying 3-methylamino-1-phenyl-1-propanol with a compound 3, namely o-halotoluene, in an inorganic base environment, resolving by L- (+) -mandelic acid to obtain a compound 4, namely R- (-) -tomoxetine-S- (+) -mandelate, refining the R- (-) -tomoxetine-S- (+) -mandelate, and converting the hydrochloride to obtain the R- (-) -atomoxetine hydrochloride.
In an embodiment of the present invention, the step of preparing 3-methylamino-1-phenyl-1-propanol using 1-phenyl-2-propenyl-1-one as a starting material (one-pot method) comprises: carrying out Aza-Michael addition reaction on the 1-phenyl-2-propenyl-1-ketone and an alcoholic solution of methylamine, adding sodium borohydride in batches when no 1-phenyl-2-propenyl-1-ketone remains, and controlling the reaction temperature to obtain the 3-methylamino-1-phenyl-1-propanol.
In some embodiments of the present invention, the 3-methylamino-1-phenyl-1-propanol involves a purification step, for example, purified water and hydrochloric acid may be added to the reaction system after the reaction is finished, and the volume ratio of the purified water to the hydrochloric acid is 5:1 (such as 10L of purified water and 2L of 2N hydrochloric acid), stirring for 20-40min, adding an extractant such as toluene for extraction, wherein the extraction can be carried out for 1 to more times (such as 2 times), combining organic phases, and washing with purified water to obtain a 3-methylamino-1-phenyl-1-propanol solution.
In the embodiment of the present invention, the addition is not a whole addition at one time, for example, the addition may be divided into 2 to more than one times, the addition may be divided into equal parts each time or may be successively increased, and the time interval of each addition may be the same or gradually shortened.
In some embodiments of the invention, the alcoholic solution of methylamine is an ethanolic solution of methylamine or a methanolic solution of methylamine. In still other embodiments, the alcoholic solution of methylamine is an alcoholic solution of methylamine at a concentration of 33% (mass concentration).
In some embodiments of the invention, the temperature of the Aza-Michael addition reaction is from 20 ℃ to 40 ℃, and in still other embodiments, from 25 ℃ to 30 ℃.
In some embodiments of the invention, the molar ratio of alcoholic solution of methylamine to 1-phenyl-2-propenyl-1-one is 1.0 to 1.5: 1; in still other embodiments, the molar ratio is 1.2 to 1.4: 1.
in some embodiments of the invention, sodium borohydride is added in portions, the reaction temperature is controlled to be-5-5 ℃; in still other embodiments, the reaction temperature is controlled to be-2 to 2 deg.C, for example, the temperature may be controlled to be-1 to 1 deg.C, 0 to 2 deg.C, or-2 to 0 deg.C.
In some embodiments of the invention, the molar ratio of 1-phenyl-2-propenyl-1-one to the total amount of sodium borohydride is 1: 1.0-1.2, and in still other embodiments, the molar ratio may be 1: 1.0, 1: 1.05, 1: 1.08, 1: 1.2.
in an embodiment of the invention, the preparation of tomoxetine mandelate (i.e., R- (-) -tomoxetine-S- (+) -mandelate) comprises: 3-methylamino-1-phenyl-1-propanol and o-halotoluene are etherified in a reaction solvent in an inorganic alkali environment by taking toluene as a water carrying agent, and the R- (-) -tomoxetine-S- (+) -mandelate is obtained by resolving and salifying mandelate (namely L- (+) -mandelic acid).
In some embodiments of the present invention, the halogen in the o-halotoluene may be F, Cl, Br, etc., and more preferably o-fluorotoluene.
In some embodiments of the invention, the reaction solvent of 3-methylamino-1-phenyl-1-propanol and o-halotoluene is a low-toxicity, high-boiling point solvent selected from one or more of ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, diethylene glycol dibutyl ether, and triethylene glycol dimethyl ether; in still other embodiments, the reaction solvent is triethylene glycol dimethyl ether.
In some embodiments of the present invention, the mass ratio of the reaction solvent selected from the group consisting of low toxicity, high boiling point solvents and 3-methylamino-1-phenyl-1-propanol is 1-5: 1; in still other embodiments, the mass ratio is 2-4: 1.
in some embodiments of the invention, the molar ratio of o-halotoluene to 3-methylamino-1-phenyl-1-propanol is from 0.8 to 4: 1; in still other embodiments, the molar ratio is 1-3: 1.
in some embodiments of the invention, the inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, and potassium carbonate; potassium hydroxide is preferred.
In some embodiments of the invention, the reaction temperature for the etherification is 100-140 ℃; in yet other embodiments, the temperature is 120-130 ℃.
In some embodiments of the invention, the process of adding mandelate for resolution to obtain R- (-) -tomoxetine-S- (+) -mandelate comprises adding L- (+) -mandelic acid after etherification reaction is finished to perform high temperature recrystallization, and comprises adding L- (+) -mandelic acid, stirring and heating to 75-80 ℃, cooling to 65-70 ℃, adding seed crystal (i.e. pure R- (-) -tomoxetine-S- (+) -mandelate), slowly cooling to room temperature, then performing crystal growth in ice-water bath at 0-5 ℃, performing suction filtration, washing filter cake with cold ethyl acetate to remove toluene, and obtaining R- (-) -tomoxetine-S- (+) -mandelate.
In an embodiment of the invention, the step of refining the R- (-) -tomoxetine-S- (+) -mandelate salt comprises high temperature recrystallization of the R- (-) -tomoxetine-S- (+) -mandelate salt in an organic solvent.
In some embodiments of the invention, the organic solvent in the refining process is ethyl acetate and/or butyl acetate; ethyl acetate is more preferred.
In some embodiments of the invention, the mass ratio of the organic solvent used during the refining to the R- (-) -tomoxetine-S- (+) -mandelate to be refined is 5 to 10: 1; in still other embodiments, the mass ratio is 7-9: 1.
in some embodiments of the invention, the high temperature recrystallization temperature is from 60 to 80 ℃; in some embodiments, the temperature is increased to 75-80 ℃ and then decreased to 65-70 ℃.
In some embodiments of the invention, the step of refining the R- (-) -tomoxetine-S- (+) -mandelate salt comprises: adding R- (-) -tomoxetine-S- (+) -mandelate and organic solvent, heating to 75-80 deg.C, cooling to 65-70 deg.C, adding crystal seed (pure R- (-) -tomoxetine-S- (+) -mandelate), and slowly cooling for crystallization. In some embodiments, the temperature is slowly reduced to 5 ℃ to precipitate crystals for growing crystals, the crystals are filtered, filter paper is rinsed by cold ethyl acetate, and the filter paper is dried in vacuum to obtain the refined R- (-) -tomoxetine-S- (+) -mandelate.
In an embodiment of the present invention, the step of converting the hydrochloride, i.e. the step of preparing R- (-) -atomoxetine hydrochloride, comprises: alkalizing, extracting, drying and dripping concentrated hydrochloric acid into the refined R- (-) -tomoxetine-S- (+) -mandelate to obtain a R- (-) -atomoxetine hydrochloride crude product, and performing high-temperature elution and crystallization on the crude product in a solvent system to obtain the R- (-) -atomoxetine hydrochloride.
In some embodiments of the present invention, the extractant used for extraction in the process of converting hydrochloride is selected from ethyl acetate and/or sec-butyl acetate; sec-butyl acetate is more preferred.
In some embodiments of the invention, the mass ratio of the extractant to R- (-) -tomoxetine-S- (+) -mandelate is 3 to 7: 1; in still other embodiments, the mass ratio is 4-6: 1.
in some embodiments of the present invention, the solvent system includes a good solvent and a poor solvent, wherein the good solvent is selected from one or more of dichloromethane, methanol and ethanol; the poor solvent is selected from ethyl acetate and/or sec-butyl acetate. In still other embodiments, the vehicle system comprises dichloromethane and ethyl acetate.
In some embodiments of the invention, the mass ratio of the good solvent to the crude R- (-) -atomoxetine hydrochloride is from 8 to 12: 1; in still other embodiments, the mass ratio is 9-11: 1.
in some embodiments of the invention, the mass ratio of the poor solvent to the crude R- (-) -atomoxetine hydrochloride is 6-12: 1; in still other embodiments, the mass ratio is 9-11: 1.
in some embodiments of the invention, the high temperature elution crystallization temperature ranges from 20 ℃ to 50 ℃; in still other embodiments, the temperature is 30-40 ℃.
In certain embodiments of the present invention, the process for preparing R- (-) -atomoxetine hydrochloride comprises: carrying out Aza-Michael addition reaction on 1-phenyl-2-propenyl-1-ketone serving as a starting material and an alcoholic solution of methylamine, adding sodium borohydride in batches when no 1-phenyl-2-propenyl-1-ketone remains, and controlling the reaction temperature to prepare 3-methylamino-1-phenyl-1-propanol; etherifying the prepared 3-methylamino-1-phenyl-1-propanol and o-halotoluene in a reaction solvent by taking the toluene as a water carrying agent in an inorganic base environment, and directly resolving and salifying the obtained product by L- (+) -mandelic acid to obtain R- (-) -tomoxetine-S- (+) -mandelate; and (2) recrystallizing the obtained R- (-) -tomoxetine-S- (+) -mandelate in an organic solvent at a high temperature for refining, alkalifying, extracting, drying and dropwise adding concentrated hydrochloric acid to form salt of the refined R- (-) -tomoxetine-S- (+) -mandelate to obtain a crude product of the R- (-) -atomoxetine hydrochloride, and carrying out high-temperature dissolution and crystallization on the crude product in a solvent system to obtain the R- (-) -atomoxetine hydrochloride.
In certain embodiments of the present invention, the process for preparing R- (-) -atomoxetine hydrochloride comprises the steps of:
slowly dripping 1-phenyl-2-propenyl-1-ketone into an alcoholic solution of methylamine, controlling the temperature to be 20-40 ℃, stirring for reaction, sampling and detecting until no 1-phenyl-2-propenyl-1-ketone remains, adding sodium borohydride in batches, controlling the system temperature to be-5-5 ℃, and controlling the molar ratio of the 1-phenyl-2-propenyl-1-ketone to the total amount of the sodium borohydride to be 1: 1.0-1.2, adding purified water and hydrochloric acid after the stirring reaction is finished, stirring, adding toluene for extraction for 2 times, combining organic phases, adding purified water for washing, and obtaining 3-methylamino-1-phenyl-1-propanol toluene solution.
Adding a solvent with low toxicity and high boiling point into the 3-methylamino-1-phenyl-1-propanol toluene solution at room temperature as a reaction solvent, such as triethylene glycol dimethyl ether, wherein the mass ratio of the reaction solvent to the 3-methylamino-1-phenyl-1-propanol is 1-5: 1, adding inorganic base such as potassium hydroxide, stirring and heating to the system temperature of 100-: 1, detecting the end point of the reaction by HPLC. And after the reaction is finished, stopping heating, cooling to 90 ℃, adding purified water into the system, separating the liquid, washing the organic phase with water, and separating the liquid to obtain a reddish brown organic layer. Transferring the oil phase, adding L- (+) -mandelic acid, stirring and heating to 75-80 ℃, then cooling to 65-70 ℃, adding seed crystal (namely pure R- (-) -tomoxetine-S- (+) -mandelate), slowly cooling to room temperature, then growing crystal in ice water bath at 0-5 ℃, filtering, washing filter cake with cold ethyl acetate to remove toluene, and obtaining white R- (-) -tomoxetine-S- (+) -mandelate solid.
Taking the R- (-) -tomoxetine-S- (+) -mandelate, adding an organic solvent (such as ethyl acetate), stirring and heating to 75-80 ℃, then cooling to 65-70 ℃, adding a seed crystal (namely pure R- (-) -tomoxetine-S- (+) -mandelate), slowly cooling to 5 ℃ for crystal growing, carrying out suction filtration, leaching with cold ethyl acetate, and carrying out vacuum drying at 45 ℃ to obtain the refined R- (-) -tomoxetine-S- (+) -mandelate.
Taking the refined R- (-) -tomoxetine-S- (+) -mandelate for alkalization, (the alkalization process can be, for example, adding a sodium hydroxide aqueous solution and stirring at 40-45 ℃), adding an extracting agent for extraction, for example, the extracting agent can be sec-butyl acetate, separating liquid after extraction is finished, washing an oil phase with water, drying and suction-filtering, washing a filter cake by using the sec-butyl acetate, combining organic phases, slowly dropwise adding concentrated hydrochloric acid at normal temperature, stirring until crystals are separated out, slowly cooling to 0-5 ℃ for crystal growth, suction-filtering, leaching the filter cake by using cold ethyl acetate, and vacuum-drying to obtain a crude product of the R- (-) -atomoxetine hydrochloride. Dissolving the crude R- (-) -atomoxetine hydrochloride product in a good solvent such as dichloromethane, wherein the mass ratio of the good solvent to the crude R- (-) -atomoxetine hydrochloride product is (8-12): slowly heating to 30-40 ℃, keeping the temperature unchanged until a poor solvent (such as ethyl acetate) is added, wherein the mass ratio of the poor solvent to the R- (-) -atomoxetine hydrochloride crude product is 6-12: 1, after the dropwise addition of the poor solvent, cooling to room temperature, cooling by using an ice water bath, growing crystals at 0-5 ℃, filtering, washing a filter cake by using ethyl acetate, and drying in vacuum to obtain a finished product of R- (-) -atomoxetine hydrochloride.
Compared with the prior art, the invention has the advantages that: the method adopts the method of directly resolving L-mandelic acid into salt, omits the oxalate refining process, shortens the reaction steps and simultaneously improves the yield, and the total yield of the method reaches 35-37 percent, which is obviously improved compared with about 30 percent reported in the literature.
In addition, the invention adopts cheap and easily available 1-phenyl-2-propenyl-1-ketone as a starting material, adopts a one-pot method to prepare 3-methylamino-1-phenyl-1-propanol, then etherifies the product with o-halotoluene (such as o-fluorotoluene) in a solvent with high boiling point and low toxicity such as triethylene glycol dimethyl ether, adds L-mandelic acid to directly split the product into salt, and obtains a target product through the steps of refining, hydrochloride conversion and the like.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this application, illustrate embodiments of the application and, together with the description, serve to explain the application and are not intended to limit the application. Embodiments of the invention are described in detail below with reference to the attached drawing figures, wherein:
FIG. 1 is a detection spectrum of a substance I of interest in the product of example 1; wherein the impurity B, D appears at 8.8min and 16.3 min;
FIG. 2 is a detection spectrum of related substance II in the product of example 1.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The reagents or starting materials used in the present invention can be purchased from conventional sources, and unless otherwise specified, the reagents or starting materials used in the present invention can be used in a conventional manner in the art or in accordance with the product specifications. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
In an embodiment of the present invention, the preparation method of R- (-) -atomoxetine hydrochloride comprises the following steps:
(1) slowly dripping compound 1, namely 1-phenyl-2-propenyl-1-ketone (the molar ratio of the alcoholic solution of methylamine to the 1-phenyl-2-propenyl-1-ketone is 1.0-1.5: 1, such as 1.2:1, 1.3:1 or 1.4: 1) into an alcoholic solution of methylamine, controlling the temperature to be 20-40 ℃ (such as 25 ℃ or 30 ℃) for stirring reaction, sampling and detecting that no 1-phenyl-2-propenyl-1-ketone remains, adding sodium borohydride in batches, controlling the temperature of the system to be-5-5 ℃ (the temperature can be-1-1 ℃, 0-2 ℃ or-2-0 ℃), and controlling the molar ratio of 1-phenyl-2-propenyl-1-ketone to the total amount of the sodium borohydride to be 1: 1.0-1.2 (the molar ratio can be 1: 1.0, 1: 1.05, 1: 1.08 and 1: 1.2), adding purified water and hydrochloric acid after stirring reaction, stirring, adding toluene for extraction for 2 times, combining organic phases, adding purified water for washing to obtain a compound 2, namely 3-methylamino-1-phenyl-1-propanol toluene solution for later use.
(2) Adding a solvent with low toxicity and high boiling point as a reaction solvent, such as triethylene glycol dimethyl ether, into the compound 2 solution obtained in the step (1), namely the 3-methylamino-1-phenyl-1-propanol toluene solution at room temperature, wherein the mass ratio of the reaction solvent to the 3-methylamino-1-phenyl-1-propanol is 1-5: 1 (such as 1:1, 1.5:1, 2:1, 3:1, 4:1 or 5:1), adding an inorganic base such as potassium hydroxide, stirring and heating to a system temperature of 100-: 1 (e.g., 0.8:1, 1:1, 1.5:1, 2:1, 3:1, or 4:1), and detecting the end point of the reaction by HPLC. And after the reaction is finished, stopping heating, cooling to 90 ℃, adding purified water into the system, separating the liquid, washing the organic phase with water, and separating the liquid to obtain a reddish brown organic layer. Transferring the oil phase, adding L- (+) -mandelic acid, stirring and heating to 75-80 deg.C (such as 75 deg.C, 78 deg.C or 80 deg.C), cooling to 65-70 deg.C (such as 65 deg.C, 66 deg.C, 68 deg.C or 70 deg.C), adding seed crystal (pure R- (-) -tomoxetine-S- (+) -mandelate), slowly cooling to room temperature, crystallizing in ice-water bath at 0-5 deg.C, vacuum filtering, washing the filter cake with cold ethyl acetate to remove toluene to obtain white R- (-) -tomoxetine-S- (+) -mandelate solid.
(3) Taking the R- (-) -tomoxetine-S- (+) -mandelate, adding an organic solvent (such as ethyl acetate), stirring, heating to 75-80 ℃ (such as the temperature can be 75 ℃, 78 ℃ or 80 ℃), then cooling to 65-70 ℃ (such as the temperature can be 65 ℃, 66 ℃, 68 ℃ or 70 ℃), adding a crystal seed (namely pure R- (-) -tomoxetine-S- (+) -mandelate), slowly cooling to 5 ℃ for crystal growing, carrying out suction filtration, leaching with cold ethyl acetate, and carrying out vacuum drying at 45 ℃ to obtain the refined R- (-) -tomoxetine-S- (+) -mandelate.
(4) Taking the refined R- (-) -tomoxetine-S- (+) -mandelate for alkalization, (the alkalization process can be, for example, adding a sodium hydroxide aqueous solution and stirring at 40-45 ℃), adding an extracting agent for extraction, for example, the extracting agent can be sec-butyl acetate, separating liquid after extraction is finished, washing an oil phase with water, drying and suction-filtering, washing a filter cake by using the sec-butyl acetate, combining organic phases, slowly dropwise adding concentrated hydrochloric acid at normal temperature, stirring until crystals are separated out, slowly cooling to 0-5 ℃ for crystal growth, suction-filtering, leaching the filter cake by using cold ethyl acetate, and vacuum-drying to obtain a crude product of the R- (-) -atomoxetine hydrochloride. Dissolving the crude R- (-) -atomoxetine hydrochloride product in a good solvent such as dichloromethane, wherein the mass ratio of the good solvent to the crude R- (-) -atomoxetine hydrochloride product is (8-12): 1 (e.g., 9:1, 10:1, or 11:1), slowly heating to 30-40 ℃ (e.g., 30 ℃, 35 ℃, or 40 ℃) and holding the temperature until a poor solvent (e.g., ethyl acetate) is added, the mass ratio of the poor solvent to the R- (-) -crude atomoxetine hydrochloride being 6-12: 1 (for example, the mass ratio is 7.2:1, 8:1 or 8.8:1), cooling to room temperature after the poor solvent is dripped, cooling by using an ice water bath, growing crystals at 0-5 ℃, filtering, washing a filter cake by using ethyl acetate, and drying in vacuum to obtain a finished product of R- (-) -atomoxetine hydrochloride.
In order to better present the technical solution of the present invention, specific examples of the preparation will be provided below.
The preparation method of the crystal seed R- (-) -tomoxetine-S- (+) -mandelate comprises the following steps:
adding 1.36kg of 33% methylamine ethanol solution into a reaction kettle, slowly dropwise adding 1.58kg of 1-phenyl-2-propenyl-1-ketone under stirring, controlling the temperature to be 25 ℃, stirring for reaction, when sampling and detecting that no raw and auxiliary materials remain, adding 0.48kg of sodium borohydride in batches, controlling the system temperature to be-1 ℃, adding 10L of purified water and 2L of 2N hydrochloric acid after stirring for reaction is finished, stirring for 30min, adding 10L of toluene for extraction twice, combining organic phases, and washing with 20L of purified water to obtain a 3-methylamino-1-phenyl-1-propanol toluene solution for later use.
Under the condition of room temperature, 4.4kg of triethylene glycol dimethyl ether and 2.39kg of KOH are added into the reaction kettle filled with the 3-methylamino-1-phenyl-1-propanol toluene solution, the mixture is stirred and heated to the system temperature of 120 ℃, the reflux water diversion is carried out for 1h, 1.32kg of o-fluorotoluene is added, the reaction lasts for about 3h, and the reaction end point is detected by HPLC. After the reaction is finished, stopping heating, cooling to 90 ℃, adding 10kg of purified water into the system, separating, washing the organic phase with 10kg of water for 2 times, and separating to obtain a reddish brown organic layer. Transferring the oil phase to a reaction kettle, adding 1.10kg of L- (+) -mandelic acid, stirring and heating to 75 ℃, then slowly cooling to room temperature, then growing crystals in ice-water bath at 0-5 ℃ for 1h, carrying out suction filtration, washing a filter cake with cold ethyl acetate to remove toluene in the filter cake, and obtaining a white R- (-) -tomoxetine-S- (+) -mandelate crude product.
Adding 1.8kg of crude mandelate and 12.6kg of ethyl acetate into a reaction kettle, stirring and heating to 75 ℃, then slowly cooling to 5 ℃ for crystal growing for 1h, carrying out suction filtration, carrying out leaching filtration by using cold ethyl acetate, and carrying out vacuum drying at 45 ℃ for more than 3h to obtain R- (-) -tomoxetine-S- (+) -mandelate, detecting according to a detection method of related substances in a test example, wherein each impurity is not more than 0.1%, the purity of a main component is more than 99.9%, if the main component is unqualified, repeatedly refining according to the refining method, and obtaining the seed crystal R- (-) -tomoxetine-S- (+) -mandelate.
Example 1
Adding 1.36kg of 33% methylamine ethanol solution into a reaction kettle, slowly dropwise adding 1.58kg of 1-phenyl-2-propenyl-1-ketone under stirring, controlling the temperature to be 25 ℃, stirring for reaction, when sampling and detecting that no raw and auxiliary materials remain, adding 0.48kg of sodium borohydride in batches, controlling the system temperature to be-1 ℃, adding 10L of purified water and 2L of 2N hydrochloric acid after stirring for reaction is finished, stirring for 30min, adding 10L of toluene for extraction twice, combining organic phases, and washing with 20L of purified water to obtain a 3-methylamino-1-phenyl-1-propanol toluene solution for later use.
Under the condition of room temperature, 4.4kg of triethylene glycol dimethyl ether and 2.39kg of KOH are added into the reaction kettle filled with the 3-methylamino-1-phenyl-1-propanol toluene solution, the mixture is stirred and heated to the system temperature of 120 ℃, the reflux water diversion is carried out for 1h, 1.32kg of o-fluorotoluene is added, the reaction lasts for about 3h, and the reaction end point is detected by HPLC. After the reaction is finished, stopping heating, cooling to 90 ℃, adding 10kg of purified water into the system, separating, washing the organic phase with 10kg of water for 2 times, and separating to obtain a reddish brown organic layer. Transferring the oil phase to a reaction kettle, adding 1.10kg of L- (+) -mandelic acid, stirring and heating to 75 ℃, adding seed crystals (purified tomoxetine mandelate) at 65 ℃, slowly cooling to room temperature, then growing crystals in an ice-water bath at 0-5 ℃ for 1h, performing suction filtration, washing a filter cake with cold ethyl acetate to remove toluene in the filter cake, and obtaining white R- (-) -tomoxetine-S- (+) -mandelate solid, wherein the yield is as follows: 42 percent.
Adding 1.8kg of mandelate and 12.6kg of ethyl acetate into a reaction kettle, stirring and heating to 75 ℃, then cooling to 65 ℃, adding seed crystals (purified tomoxetine mandelate), slowly cooling to 5 ℃, growing crystals for 1h, performing suction filtration, leaching with cold ethyl acetate, and performing vacuum drying at 45 ℃ for more than 3h to obtain a refined R- (-) -tomoxetine-S- (+) -mandelate product with yield: 93 percent.
Adding 1.62kg of R- (-) -tomoxetine-S- (+) -mandelate and 11.34kg of purified water (7 times of volume-to-mass ratio) into a reaction kettle, dissolving 0.24kg of NaOH in 1.62kg of water, adding the mixture into the reaction kettle, stirring for 10 minutes at 40-45 ℃, adding 6.48kg of sec-butyl acetate, separating, washing the oil phase with 2kg of purified water for 3 times respectively, transferring the oil phase to the reaction kettle, adding 0.9kg of anhydrous magnesium sulfate, stirring and drying for 30min, performing suction filtration, washing a filter cake twice with 1kg of sec-butyl acetate respectively, combining organic phases, transferring the organic phases into the reaction kettle, slowly dripping concentrated hydrochloric acid at normal temperature after finishing dripping within 1h, stirring until crystals are separated out, slowly cooling to 0-5 ℃ for crystal growth for 1 hour, performing suction filtration, rinsing the filter cake with cold ethyl acetate for 2 times, performing vacuum drying for 3 hours at 50 ℃ to obtain a white R- (-) -atomoxetine hydrochloride crude product, yield: 94 percent.
Adding 1.05kg of the crude product into a reaction kettle, dissolving the crude product by using 9.45kg of dichloromethane, slowly heating the mixture to 30 ℃, keeping the temperature constant, directly adding 1.89kg of ethyl acetate, adding a seed crystal (purified R- (-) -atomoxetine hydrochloride), then slowly dropwise adding 7.56kg of ethyl acetate, finishing dropwise adding in 2h, cooling the mixture to room temperature after the dropwise adding is finished, cooling the mixture by using an ice water bath, growing crystals at 0-5 ℃ for 1h, performing suction filtration, washing a filter cake twice by using ethyl acetate, and performing vacuum drying at 50 ℃ for 3h to obtain a R- (-) -atomoxetine hydrochloride finished product, wherein the yield is as follows: 95 percent.
Example 2
Adding 1.36kg of 33% methylamine ethanol solution into a reaction kettle, slowly dropwise adding 1.58kg of 1-phenyl-2-propenyl-1-ketone under stirring, controlling the temperature to be 25 ℃, stirring for reaction, when sampling and detecting that no raw and auxiliary materials remain, adding 0.49kg of sodium borohydride in batches, controlling the system temperature to be 0-2 ℃, adding 10L of purified water and 2L of 2N hydrochloric acid after stirring for reaction is finished, stirring for 30min, adding 15L of toluene for extraction twice, combining organic phases, and washing with 20L of purified water to obtain a 3-methylamino-1-phenyl-1-propanol toluene solution for later use.
Under the condition of room temperature, 6.6kg of triethylene glycol dimethyl ether and 2.39kg of KOH are added into the reaction kettle filled with the 3-methylamino-1-phenyl-1-propanol toluene solution, the mixture is stirred and heated to the system temperature of 125 ℃, water is distributed for 1 hour under reflux, 2.6kg of o-fluorotoluene is added, the reaction lasts for about 2 hours, and the reaction end point is detected by HPLC. After the reaction is finished, stopping heating, cooling to 90 ℃, adding 10kg of purified water into the system, separating, washing the organic phase with 10kg of water for 2 times, and separating to obtain a reddish brown organic layer. Transferring the oil phase to a reaction kettle, adding 1.10kg of L- (+) -mandelic acid, stirring and heating to 78 ℃, adding seed crystals at 66 ℃, slowly cooling to room temperature, then growing crystals in ice-water bath at 0-5 ℃ for 1h, performing suction filtration, washing a filter cake with cold ethyl acetate to remove toluene in the filter cake, and obtaining white R- (-) -tomoxetine-S- (+) -mandelate solid, wherein the yield is as follows: 44 percent.
Adding 1.8kg of mandelate and 14.4kg of ethyl acetate into a reaction kettle, stirring and heating to 78 ℃, then cooling to 68 ℃, adding seed crystals (purified tomoxetine mandelate), slowly cooling to 5 ℃, growing crystals for 1h, performing suction filtration, leaching a filter cake by using cold ethyl acetate, and performing vacuum drying at 45 ℃ for more than 3h to obtain a refined R- (-) -tomoxetine-S- (+) -mandelate product, wherein the yield is as follows: 92 percent.
Adding 1.62kg of R- (-) -tomoxetine-S- (+) -mandelate and 11.34kg of purified water (7 times of volume-to-mass ratio) into a reaction kettle, dissolving 0.24kg of NaOH in 1.62kg of water, adding the mixture into the reaction kettle, stirring for 10 minutes at 40-45 ℃, adding 8.1kg of sec-butyl acetate, separating, washing the oil phase with 2kg of purified water for 3 times respectively, transferring the oil phase to the reaction kettle, adding 0.9kg of anhydrous magnesium sulfate, stirring and drying for 30min, performing suction filtration, washing a filter cake twice with 1.25kg of sec-butyl acetate respectively, combining organic phases, transferring the organic phases into the reaction kettle, slowly dripping concentrated hydrochloric acid into the reaction kettle at normal temperature after finishing dripping within 1 hour, stirring until crystals are separated out, slowly cooling to 0-5 ℃ for crystal growth for 1 hour, performing suction filtration, leaching the filter cake with cold ethyl acetate for 2 times, performing vacuum drying for 3 hours at 50 ℃ to obtain a white R- (-) -atomoxetine hydrochloride crude product, yield: 92 percent.
Adding 1.05kg of the crude product into a reaction kettle, dissolving the crude product by using 10.5kg of dichloromethane, slowly heating the mixture to 35 ℃, keeping the temperature constant, directly adding 2.1kg of ethyl acetate, adding seed crystals (purified R- (-) -atomoxetine hydrochloride), slowly dropwise adding 8.4kg of ethyl acetate, cooling the mixture to room temperature after dropwise adding within 2h, cooling the mixture by using an ice water bath, growing crystals at 0-5 ℃ for 1h, carrying out suction filtration, and washing a filter cake twice by using ethyl acetate. Vacuum drying at 50 ℃ for 3h to obtain a finished product of R- (-) -atomoxetine hydrochloride, wherein the yield is as follows: 96 percent.
Example 3
Adding 1.36kg of 33% methylamine ethanol solution into a reaction kettle, slowly dropwise adding 1.58kg of 1-phenyl-2-propenyl-1-ketone under stirring, controlling the temperature to be 25 ℃, stirring for reaction, when sampling and detecting that no raw and auxiliary materials remain, adding 0.49kg of sodium borohydride in batches, controlling the system temperature to be-2-0 ℃, adding 10L of purified water and 2L of 2N hydrochloric acid after stirring for reaction is finished, stirring for 30min, adding 20L of toluene for extraction twice, combining organic phases, and washing with 40L of purified water to obtain a 3-methylamino-1-phenyl-1-propanol toluene solution for later use.
Under the condition of room temperature, 8.8kg of triethylene glycol dimethyl ether and 2.39kg of KOH are added into the reaction kettle filled with the 3-methylamino-1-phenyl-1-propanol toluene solution, the mixture is stirred and heated to the system temperature of 130 ℃, water is distributed for 1 hour under reflux, 6.66kg of o-fluorotoluene is added, the reaction lasts for about 1.5 hours, and the reaction end point is detected by HPLC. After the reaction is finished, stopping heating, cooling to 90 ℃, adding 10kg of purified water into the system, separating, washing the organic phase with 10kg of water for 2 times, and separating to obtain a reddish brown organic layer. Transferring the oil phase to a reaction kettle, adding 1.10kg of L- (+) -mandelic acid, stirring and heating to 80 ℃, adding seed crystals (purified tomoxetine mandelate) at 70 ℃, slowly cooling to room temperature, then growing crystals in an ice-water bath at 0-5 ℃ for 1h, performing suction filtration, washing a filter cake with cold ethyl acetate to remove toluene in the filter cake, and obtaining white R- (-) -tomoxetine-S- (+) -mandelate solid, wherein the yield is as follows: 45 percent.
Adding 1.8kg of mandelate and 16.2kg of ethyl acetate into a reaction kettle, stirring and heating to 80 ℃, then cooling to 70 ℃, adding seed crystals (purified tomoxetine mandelate), slowly cooling to 5 ℃, growing crystals for 1h, performing suction filtration, leaching a filter cake by using cold ethyl acetate, and performing vacuum drying at 45 ℃ for more than 3h to obtain a refined R- (-) -tomoxetine-S- (+) -mandelate product, wherein the yield is as follows: 92 percent.
Adding 1.62kg of R- (-) -tomoxetine-S- (+) -mandelate and 11.34kg of purified water (7 times of volume-to-mass ratio) into a reaction kettle, dissolving 0.24kg of NaOH in 1.62kg of water, adding the mixture into the reaction kettle, stirring for 10 minutes at 40-45 ℃, adding 9.72kg of sec-butyl acetate, separating, washing the oil phase with 2kg of purified water for 3 times, transferring the oil phase to the reaction kettle, adding 0.9kg of anhydrous magnesium sulfate, stirring and drying for 30min, performing suction filtration, washing a filter cake twice with 1kg of sec-butyl acetate, combining organic phases, transferring the organic phases into the reaction kettle, slowly dripping concentrated hydrochloric acid at normal temperature after finishing dripping within 1h, stirring until crystals are separated out, slowly cooling to 0-5 ℃ for crystal growth for 1 hour, performing suction filtration, rinsing the filter cake with cold ethyl acetate for 2 times, performing vacuum drying for 3 hours at 50 ℃ to obtain a white R- (-) -atomoxetine hydrochloride crude product, yield: 91 percent.
Adding 1.05kg of the crude product into a reaction kettle, dissolving the crude product with 11.55kg of dichloromethane, slowly heating the mixture to 40 ℃, keeping the temperature constant, directly adding 2.31kg of ethyl acetate, adding seed crystals (purified R- (-) -atomoxetine hydrochloride), slowly dropwise adding 9.24kg of ethyl acetate, after dropwise adding, cooling the mixture to room temperature after the dropwise adding is finished, cooling the mixture by using an ice water bath, growing crystals at 0-5 ℃ for 1 hour, performing suction filtration, and washing a filter cake twice by using ethyl acetate. Vacuum drying at 50 ℃ for 3h to obtain a finished product of R- (-) -atomoxetine hydrochloride, wherein the yield is as follows: 94 percent.
Comparative example
The method is carried out according to the method in the comparative example, wherein the method comprises the following steps:
20g of 3-methylamino-1-phenylpropanol was dissolved in 100mL of dichloromethane, 28.8g of di-tert-butyl dicarbonate was added, and the reaction was stirred at 35 ℃ for 1 hour. Evaporating dichloromethane, adding 300ml of toluene for dissolving, sequentially adding 23.0g of diethyl azodicarboxylate and 14.3g of o-fluorotoluene, slowly adding 43.6g of triphenylphosphine, stirring at room temperature for reaction for 24 hours to generate a large amount of white powder, stopping the reaction, performing suction filtration to obtain a white powder solid and a pale yellow solution, washing the solution after suction filtration twice with a sodium carbonate solution, washing twice with a dilute hydrochloric acid solution, washing twice with n-hexane, washing once with saturated salt, drying with anhydrous sodium sulfate, concentrating, cooling to separate out 35.4g of white crystals, and obtaining the yield of 83.6%.
Putting 15g of the product in the previous step into a 100mL round-bottom flask, adding 50mL of water, adjusting the pH to 8-9 by using a sodium carbonate solution, extracting by using xylene (30mL multiplied by 3), washing the xylene extract by using saturated sodium chloride (15mL multiplied by 2), drying by using anhydrous magnesium sulfate, filtering, adding xylene containing L (+) mandelic acid into the filtrate, stirring for 3 hours at room temperature, adding diethyl ether to precipitate a solid, filtering, washing and drying to obtain 9.3g of white (+) - [ R-tomoxetine-S-mandelate ] crystals, wherein the yield is 38.8%.
Putting 8g of (+) - [ R-tomoxetine-S-mandelate ] crystal into a 100mL reaction bottle, adding 30mL of water, adjusting the pH value to 9 with NaOH solid, extracting with diethyl ether (30mL multiplied by 3), combining extracts, washing with saturated saline (15mL multiplied by 3), drying with anhydrous magnesium sulfate, filtering, adding 30% HCl-diethyl ether solution into diethyl ether filtrate, adjusting the pH value to 2-3, standing at the temperature of 0-5 ℃ for 1h, and collecting white solid; recrystallizing with dichloromethane and ethyl acetate, and vacuum drying to obtain white atomoxetine hydrochloride product 4.8g with yield of 84.0%.
Test examples
The known main impurities of R- (-) -atomoxetine hydrochloride are A-E, and the chemical name and the structural formula are as follows:
a related substance I: detection conditions and method for impurity A and impurity E
A chromatographic column: c18 column, 250mm × 4.6mm, particle size 5 μm
Detection wavelength: 210nm
Column temperature: 30 deg.C
Flow rate: 1ml/min
Sample introduction volume: 20 μ l
Operating time: 55min
Buffer solution: 12.8g/L sodium dihydrogen phosphate aqueous solution was prepared, and 4.3g of the above solution was added to 1L of the solution
Adjusting pH of sodium octyl sulfonate to 2.8 with phosphoric acid, filtering, and performing ultrasonic treatment.
Mobile phase A: acetonitrile buffer 3:5
Mobile phase B: acetonitrile methanol buffer 8:5:6
And (3) dissolving phase: mobile phase A. mobile phase B is 3:1
And (3) an elution mode: gradient elution
TABLE 1 gradient elution procedure for substance I analysis
| Time (min) | Solution A (%) | Solution B (%) |
| 0 | 90 | 10 |
| 10 | 60 | 40 |
| 15 | 50 | 50 |
| 20 | 40 | 60 |
| 25 | 30 | 70 |
| 40 | 30 | 70 |
| 45 | 90 | 10 |
| 55 | 90 | 10 |
System applicability test solution: a tomoxetine hydrochloride sample, an appropriate amount of impurity A, an appropriate amount of impurity D and an appropriate amount of impurity E are prepared into a mixed solution containing about 1.0mg of tomoxetine hydrochloride and each impurity thereof (the amount of the impurity is the limit of each impurity respectively) per 1ml by using the dissolved phase as a system applicability test solution.
Test solution: weighing about 10mg of the tomoxetine hydrochloride test sample, precisely weighing, placing in a 10ml measuring flask, adding a dissolving phase to dilute and dissolve, and fixing the volume to a scale.
Control solution: precisely sucking 0.5ml of a sample solution, placing the sample solution in a 50ml volumetric flask, adding a dissolving phase to dilute and dissolve the sample solution, and fixing the volume to a scale; precisely transferring 1.0ml of the solution, putting the solution into a 10ml volumetric flask, adding a dissolving phase to dilute and dissolve the solution, and fixing the volume to a scale to obtain the product.
In the system applicability test, 20 mul of each solution phase and the system applicability test solution are injected into a sample and respectively injected into a liquid chromatograph; the separation degree R between the main peak and the adjacent peak (impurity D) is more than or equal to 1.5, the separation degree R between the impurity A peak and the impurity E peak is more than or equal to 1.5, the theoretical plate number N of the main peak is more than or equal to 3000, and the tailing factor T of the main peak is less than or equal to 2.0.
The determination method comprises the following steps: respectively injecting 20 μ l of each of the test solution and the control solution into a liquid chromatograph, and recording the chromatogram; deducting the chromatographic peaks of the blank solvent and the impurity D, wherein the impurity A and the impurity E are not more than 1.0 time (0.10%) of the main peak area of the control solution; the peak area of other single impurities is not more than 1.0 time (0.10%) of the main peak area of the control solution; the sum of the corrected peak areas for each impurity must not be greater than 5 times (0.50%) the main peak area of the control solution.
In the above formula:
Fi: relative response factors of the impurity A and the impurity E;
Ai: peak areas of impurity A and impurity E in the test solution;
Acontrol solution: peak area of main peak in control solution;
Aother total impurities: and (3) removing the blank solvent, the impurity A, the impurity D and the impurity E, and then summing the peak areas of all the impurities.
Related substance II: detection condition and method for impurity B, C, D, S-isomer
A chromatographic column: CHIRALCEL AD-H4.6 mm 250mmL particle size 5 μm
Detection wavelength: 273nm
Column temperature: 25 deg.C
Sample introduction amount: 20 μ l
Flow rate: 1.0ml/min
Mobile phase: n-hexane, n-propanol, anhydrous ethanol, diethylamine, 95:3:2:0.3
And (3) dissolving phase: anhydrous ethanol n-hexane 28:72
Respectively and precisely weighing appropriate amount of impurity B, impurity C and impurity D, S-isomer working reference substances, dissolving with a solvent, and diluting to obtain an impurity reference substance mixed solution containing about 20 μ g of each of impurity B, impurity C and impurity D and about 30 μ g of S-isomer per 1 ml.
Taking about 20mg of the tomoxetine hydrochloride sample, precisely weighing, placing in a 10ml measuring flask, precisely sucking 1ml of the reference substance stock solution into the same measuring flask, dissolving and diluting by using a dissolving phase, and fixing the volume to a scale to be used as a system applicability solution.
Taking about 20mg of the tomoxetine hydrochloride sample, precisely weighing, putting into a 10ml measuring flask, dissolving and diluting by using a dissolving phase, and fixing the volume to a scale to be used as a sample solution.
Precisely sucking 0.5ml of a sample solution, placing the sample solution in a 50ml volumetric flask, adding a dissolving phase to dilute and dissolve the sample solution, and fixing the volume to a scale; precisely transferring 1.0ml of the solution, placing the solution in a 10ml volumetric flask, adding a dissolving phase to dilute and dissolve the solution, and fixing the volume to a scale to obtain a control solution.
In the system applicability test, 20 mul of each solution phase and the system applicability test solution are injected into a sample and respectively injected into a liquid chromatograph; the separation degree R of the main peak and the adjacent peak (S-isomer) is more than or equal to 1.5, and the tailing factor T of the main peak is less than or equal to 2.0.
The determination method comprises the following steps: respectively injecting 20 μ l of each of the test solution and the control solution into a liquid chromatograph, and recording the chromatogram; after deducting the blank solvent chromatographic peak, the impurity B and the impurity C are not more than 1.0 time (0.1%) of the main peak area of the control solution; the impurity D, S-isomer should not be larger than 1.0 times (0.10%) and 1.5 times (0.15%) of the main peak area of the control solution, respectively.
In the above formula:
Fi: relative response factors of the impurity B, the impurity C and the impurity D, S-isomer are 1.18, 1.22, 1.0 and 1.0 respectively;
Ai: peak areas of a substance B, an impurity C and an impurity D, S-isomer in the test solution;
Acontrol solution: main peak area in control solution.
The finished products of R- (-) -atomoxetine hydrochloride prepared in examples 1 to 3 and the comparative example were tested according to the above test methods and conditions, and the results were as follows:
TABLE 2 detection results of related substances of R- (-) -atomoxetine hydrochloride
The detection patterns of related substance I and related substance II of the finished product in example 1 are shown in FIGS. 1 and 2.
As can be seen from Table 2, examples 1 to 3 were not significantly different from the comparative examples for the related substance I (impurity A and impurity E), but the comparative examples were compared with examples 1 to 3 for the related substance II (impurity B, C, D) in which impurity C was detected and the amount of impurity B, D was also higher than those of examples 1 to 3; for the results of the normal phase detection, the yield of the comparative example was 27.2% and the purity was 99.69%, which was substantially the same as the yield of about 30% and the purity of 99.85% reported in the literature, according to the above detection method; from the aspect of yield, the total yield of the preparation method is improved by about 7-9% compared with the proportion, the production cost is effectively reduced, and the preparation method has obvious advantages as a whole.
Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (16)
1. A preparation method of R- (-) -atomoxetine hydrochloride is characterized in that 1-phenyl-2-propenyl-1-ketone is used as a starting material to perform Aza-Michael addition reaction with an alcohol solution of methylamine, when no 1-phenyl-2-propenyl-1-ketone remains, sodium borohydride is added in batches, the reaction temperature is controlled, and 3-methylamino-1-phenyl-1-propanol is prepared by a one-pot method; etherifying the prepared 3-methylamino-1-phenyl-1-propanol and o-halotoluene in a reaction solvent by taking the toluene as a water carrying agent in an inorganic base environment, and directly resolving and salifying the obtained product by L- (+) -mandelic acid to obtain R- (-) -tomoxetine-S- (+) -mandelate; recrystallizing the obtained R- (-) -tomoxetine-S- (+) -mandelate in an organic solvent at a high temperature for refining, and transferring the refined R- (-) -tomoxetine-S- (+) -mandelate into hydrochloride to obtain R- (-) -atomoxetine hydrochloride;
the reaction solvent is selected from one or more of ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, diethylene glycol dibutyl ether and triethylene glycol dimethyl ether;
the reaction temperature of the etherification is 100-140 ℃;
the temperature of the high-temperature recrystallization is 60-80 ℃;
the organic solvent in the refining process is ethyl acetate and/or butyl acetate.
2. The process of claim 1, wherein the alcohol solution of methylamine is an ethanol solution of methylamine or a methanol solution of methylamine.
3. The process of claim 1, wherein the temperature of the Aza-Michael addition reaction is 20-40 ℃.
4. The process of claim 1, wherein sodium borohydride is added in portions, and the reaction temperature is controlled to be-5 to 5 ℃.
5. The process of claim 1, wherein the molar ratio of 1-phenyl-2-propenyl-1-one to the total amount of sodium borohydride is 1: 1.0-1.2.
6. The method for preparing R- (-) -atomoxetine hydrochloride according to claim 1, wherein the mass ratio of the reaction solvent to 3-methylamino-1-phenyl-1-propanol is 1-5: 1.
7. the process of claim 1, wherein the molar ratio of o-halotoluene to 3-methylamino-1-phenyl-1-propanol is 0.8 to 4: 1.
8. the process of claim 1, wherein the inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, and potassium carbonate.
9. The preparation method of R- (-) -atomoxetine hydrochloride according to claim 1, wherein the mass ratio of the organic solvent to R- (-) -tomoxetine-S- (+) -mandelate in the refining process is 5-10: 1.
10. The process of claim 1, wherein the step of refining the R- (-) -tomoxetine-S- (+) -mandelate comprises: adding R- (-) -tomoxetine-S- (+) -mandelate and an organic solvent, firstly heating to 75-80 ℃, then cooling to 65-70 ℃, adding seed crystals, and slowly cooling for crystallization.
11. The process of claim 1, wherein the step of converting the hydrochloride comprises: alkalizing, extracting, drying and dripping concentrated hydrochloric acid into refined R- (-) -tomoxetine-S- (+) -mandelate to obtain R- (-) -atomoxetine hydrochloride crude product, and performing high-temperature elution and crystallization on the crude product in a solvent system to obtain R- (-) -atomoxetine hydrochloride; the temperature range of the high-temperature elution crystallization is 20-50 ℃.
12. The process of claim 11, wherein the extraction solvent used in the conversion to the hydrochloride is selected from ethyl acetate and/or sec-butyl acetate.
13. The method of claim 12, wherein the mass ratio of the extractant to the R- (-) -tomoxetine-S- (+) -mandelate is 3-7: 1.
14. the method for preparing R- (-) -atomoxetine hydrochloride according to claim 11, wherein the solvent system comprises a good solvent and a poor solvent, wherein the good solvent is one or more of dichloromethane, methanol and ethanol; the poor solvent is ethyl acetate and/or sec-butyl acetate.
15. The method for preparing R- (-) -atomoxetine hydrochloride according to claim 14, wherein the mass ratio of the good solvent to the crude R- (-) -atomoxetine hydrochloride is 8-12: 1.
16. the method for preparing R- (-) -atomoxetine hydrochloride according to claim 14, wherein the mass ratio of the poor solvent to the crude R- (-) -atomoxetine hydrochloride is 6-12: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910506272.1A CN110194719B (en) | 2019-06-12 | 2019-06-12 | Preparation method of R- (-) -atomoxetine hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910506272.1A CN110194719B (en) | 2019-06-12 | 2019-06-12 | Preparation method of R- (-) -atomoxetine hydrochloride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110194719A CN110194719A (en) | 2019-09-03 |
| CN110194719B true CN110194719B (en) | 2020-05-15 |
Family
ID=67754460
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910506272.1A Active CN110194719B (en) | 2019-06-12 | 2019-06-12 | Preparation method of R- (-) -atomoxetine hydrochloride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110194719B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111302958B (en) * | 2020-03-24 | 2023-05-02 | 合肥医工医药股份有限公司 | Preparation method of optically pure (R) -N-methyl-3-phenyl-3- (o-tolyloxy) -propylamine hydrochloride |
| CN113219094A (en) * | 2021-05-07 | 2021-08-06 | 湖北欣泽霏药业有限公司 | Liquid chromatography detection method for optical isomer of tomoxetine hydrochloride oral solution |
| CN113358773B (en) * | 2021-05-21 | 2022-09-13 | 健民药业集团股份有限公司 | Reversed phase liquid chromatography method for detecting atomoxetine hydrochloride enantiomer |
| CN113527114A (en) * | 2021-06-15 | 2021-10-22 | 海南卓科制药有限公司 | Preparation method of tomoxetine hydrochloride |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2101650B1 (en) * | 1995-06-29 | 1998-01-16 | Lilly Sa | PROCEDURE FOR THE PREPARATION OF N-METHYL-3-PHENYL-3- (P-TRIFLUOROMETHYLPHENOXY) PROPYLAMINE. |
| WO2006004976A2 (en) * | 2004-06-28 | 2006-01-12 | Teva Pharmaceutical Fine Chemicals S.R.L. | Process for the preparation of atomoxetine hydrochloride |
| CN1942429A (en) * | 2004-06-28 | 2007-04-04 | 特瓦药物精化学品股份有限公司 | Processes for the preparation of tomoxetine |
-
2019
- 2019-06-12 CN CN201910506272.1A patent/CN110194719B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2101650B1 (en) * | 1995-06-29 | 1998-01-16 | Lilly Sa | PROCEDURE FOR THE PREPARATION OF N-METHYL-3-PHENYL-3- (P-TRIFLUOROMETHYLPHENOXY) PROPYLAMINE. |
| WO2006004976A2 (en) * | 2004-06-28 | 2006-01-12 | Teva Pharmaceutical Fine Chemicals S.R.L. | Process for the preparation of atomoxetine hydrochloride |
| CN1942429A (en) * | 2004-06-28 | 2007-04-04 | 特瓦药物精化学品股份有限公司 | Processes for the preparation of tomoxetine |
Non-Patent Citations (3)
| Title |
|---|
| A Michael Addition−Asymmetric Transfer Hydrogenation One-Pot Enantioselective Tandem Process for Syntheses of Chiral γ‑Secondary Amino Alcohols;Liang Wu等;《Org. Lett.》;20170531;第19卷(第12期);第3047-3050页 * |
| 抗抑郁药盐酸托莫西汀的合成新工艺;何晓强;《中国药学杂志》;20100731;第45卷(第14期);第1104-1106页 * |
| 新型儿童多动症治疗药物盐酸托莫西汀的研制;王玲;《山东大学硕士学位论文》;20140415;第18-50页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110194719A (en) | 2019-09-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110194719B (en) | Preparation method of R- (-) -atomoxetine hydrochloride | |
| CN101717392A (en) | Method for preparing rotigotine and derivative thereof | |
| JP6852215B2 (en) | Voglibose Impurity I Hydrochloride Preparation Method | |
| CN115286521B (en) | Synthesis method of levosalbutamol hydrochloride | |
| CN104263797A (en) | Preparation method of R-1-aminotetralin | |
| CN106565688B (en) | Pazopanib dimer and its preparation method and application | |
| Hou et al. | Squaramide-catalysed asymmetric Michael addition/cyclization cascade reaction of 4-arylmethylidene-2, 3-dioxopyrrolidines with 2-isothiocyanato-1-indanones | |
| CN109485638A (en) | A kind of uncommon preparation method for Buddhist nun's intermediate difficult to understand | |
| CN108017619B (en) | Topiroxostat impurity and preparation method thereof | |
| CN109608468A (en) | Tofacitinib citrate impurity, and synthesis method and application thereof | |
| CN113956197A (en) | Preparation method of chlorpheniramine maleate impurity | |
| CN110372557B (en) | Cyclohexanamines D3/D2Partial receptor agonists | |
| CN101955480B (en) | Pyrazolo [3,4-b] quinoline compound and preparation method thereof | |
| CN110698445B (en) | 3-amine alkyl phthalide compound, preparation method and application thereof | |
| CN110218189B (en) | Abelide intermediate and simple preparation method of Abelide | |
| CN106397227A (en) | Preparation method of dapoxetine hydrochloride | |
| CN106243050B (en) | A kind of method of suitable industrialized production Clobazam | |
| CN103596927A (en) | Novel process for the synthesis of 7-chloro-4-(piperazin-1-yl)-quinoline | |
| CN110041180A (en) | Alkannin 9 oxime derivate of nitrogen-containing hetero side chain and preparation method thereof and medical usage | |
| CN104387284A (en) | Synthesis methods of D9-clenbuterol hydrochloride labeled by deuterium and synthesis intermediate thereof | |
| CN114685349B (en) | Process for preparing cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide | |
| EP2389354A1 (en) | 2-{2-amino-3-ýhydroxy(phenyl)methyl¨phenyl} acetamide | |
| CN113563285A (en) | Preparation method of novel medicine Vothiocetin for treating major depressive disorder | |
| CN111670191B (en) | Crystal form of pyridone derivative, preparation method and application | |
| CN111233820B (en) | Fingolimod derivative containing crown ether and di (2-methoxyethoxy) structure |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |