CN110194719A - A kind of preparation method in R- (-)-levels Moses spit of fland - Google Patents
A kind of preparation method in R- (-)-levels Moses spit of fland Download PDFInfo
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- CN110194719A CN110194719A CN201910506272.1A CN201910506272A CN110194719A CN 110194719 A CN110194719 A CN 110194719A CN 201910506272 A CN201910506272 A CN 201910506272A CN 110194719 A CN110194719 A CN 110194719A
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- 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
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- 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
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- 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
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- 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
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- 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
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- 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
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- 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
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Abstract
The present invention provides a kind of preparation method in R- (-)-levels Moses spit of fland, 3- methylamino -1- phenyl-1-propanol is prepared by starting material of 1- phenyl -2- acrylic -1- ketone in this method, then 3- methylamino -1- phenyl-1-propanol is etherified under inorganic base environment with adjacent toluene halide, is split to obtain R- (-)-atomoxetine-S- (+)-mandelate and then purification R- (-)-atomoxetine-S- (+)-mandelate through L- (+)-mandelic acid, is turned hydrochloride up to R- (-)-levels Moses spit of fland.Method of the invention eliminates intermediate one step of oxalic acid salt refining, reduces reaction step, has many advantages, such as that supplementary material is cheap and easy to get, side reaction is few, action solvent toxicity is low, high income, purity is high, at low cost, suitable industrialization production.
Description
Technical field
The present invention relates to field of medicaments, and in particular to a kind of preparation method in R- (-)-levels Moses spit of fland.
Background technique
Disclosing the information of the background technology part, it is only intended to increase understanding of the overall background of the invention, without certainty
It is considered as recognizing or implying in any form that information composition has become existing skill well known to persons skilled in the art
Art.
Children with attention deficit hyperactivity disorder (Attention Deficit Hyperactivity Disorder, ADHD)
Common a kind of mental handicape childhood China is known as hyperactivity, is is shown as and age and the disproportionate note of developmental level
Meaning power does not collect neutralization and pays attention to of short duration time, hyperactivity hyperkinesia and impulsion, is often accompanied by difficulty of learning, conduct disorder and maladjustment.It should
The a lot of diseases of symptom are before 7 years old, to the cognition of infant, mood, behavior, quality of life and social function long lasting effect, while mostly
Number suffers from other class behaviors or emotional problem/obstacle altogether.
Tomoxetine hydrochloride (CAS:82248-59-7), chemical name are (-)-N- methyl -3- phenyl -3- (O- oxygen first
Benzene)-propylamin hydrochloride, structural formula is as follows.
The medicine is developed by Lilly company, and tasteable drug administration (FDA) approval, in January, 2003 are obtained in July, 2002
It lists in the U.S., for a kind of selective norepinephrine cell reabsorption inhibitor, pays attention to for children and adolescents and adult patient
The treatment of power defect obstacle (hyperactivity) is the first non-central excitatory medicine that FDA ratifies in this field in recent ten years
Object.Mechanism of action is to inhibit nerve cell to the reuptake of serotonin (5-HT), improves concentration of the 5-HT in synaptic cleft,
So as to improve the mood of patient.Such drug selectivity is strong, and cholinergic Small side effects, curative effect is suitable with tricyclic drugs, and
Adverse reaction is significantly less than tricyclic drugs.The market ADHD is mainly monopolized by excitant similar drug at present, as Novartis Co., Ltd/
The methylphenidate (methylphenidate, Ritalin) of Celgene company.Tomoxetine hydrochloride removes first kidney as a kind of selectivity
Upper parathyrine cell reabsorption inhibitor, incitantia can be replaced by providing the first by patient, the alternative medicine that can irregularly use
Object has preferable market prospects.
About the preparation of tomoxetine hydrochloride, mainly there are chemical synthesis and Microbe synthesis two major classes, wherein chemistry closes
At method due to its chiral centre, mainly there are two paths of mesotomy method and dissymmetric synthesis；Microbe synthesis is also first
Prepare chiral centre: the γ-chiral amino alcohol, including lipase fractionation, resting cell etc. that N replaces, then using etherificate
Or other chemical reactions obtain.Microorganism catalysis method has the advantages such as safe and environment-friendly, but presently relevant research is answered also in basis
With research, there are also more problem is to be solved in terms of extensive industrialization；Dissymmetric synthesis using chirality due to being matched in chemical method
Body, costly, there is also certain deficiencies in terms of industrialization for price.
Inventors have found that tomoxetine hydrochloride industrialization route is first prepared still based on chemical resolution method at present
Tomoxetine hydrochloride raceme, then obtains through chiral resolutions such as L- mandelic acids, mainly there is following several routes:
Route one: U.S.Pat.No.4314081, Chinese journal of Medicinal Chemistry, 2005 (15) 5:282-284
Using 3- chlorobenzene propane as starting material, γ-bromo-derivative is prepared using N- bromo-succinimide (NBS) bromo, with
Next door phenol etherification reaction, then reacts 12h with methylamine water solution at 140 DEG C, tomoxetine hydrochloride raceme is obtained, through tearing open
Divide, obtain finished product at salt.But the route, since amination is high temperature, reaction under high pressure, there are greater risks for operational safety；Simultaneously
Halides are likely to occur elimination reaction under basic conditions, generate by-product.
Route two: U.S.Pat.No.4314081
Using N, TMSDMA N dimethylamine base propiophenone is that starting material is obtained through reduction, chloro, nucleophilic displacement of fluorine, demethylation
Atomoxetine raceme is split, obtains finished product at salt.But demethylation uses toxic articles cyanogen bromide during being somebody's turn to do, and is grasping
There are larger security risks on work.
Route three: WO2015001565
Using 3- chloro-1-phenyl -1- acetone as starting material, through reduction obtain 3- chloro-1-phenyl -1- propyl alcohol, then with first
3- methylamino -1- phenyl-1-propanol is prepared in amine aqueous solution, and the purity of the step product is lower (about 85%), causes subsequent
Purifying is more difficult, while the time needed for low temperature amination is longer, and when high temperature needs reaction under high pressure；Then with next door phenol or
O-fluorotobuene etherificate, etherificate are catalyzed using organic base (such as tert-butyl alcohol)；And with DMAC N,N' dimethyl acetamide, N- in the route
Methyl pyrrolidone is solvent, and used solvent toxicity is relatively strong (N-Methyl pyrrolidone has certain dermal toxicity), and
It is expensive, cause higher cost.
Route four: Chinese Pharmaceutical Journal, 2010,45 (14): 1104-1106. Chemical Industry in Guangzhou, 2015, (22): 51-53.
Using inexpensive acetophenone as raw material, through Mannich reaction, reduction gained, but the route by-product is more, especially exists
During Mannich reaction prepares 3- methylamino -1- phenyl -1- propanone hydrochloride, it is relatively easy to form three-level Mannich base by-product
Object, shown in following route, although metamfepramone can be converted by three-level Mannich base by-product by steam distillation,
Energy consumption is higher during being, yield is also only 85% or so.
Three-level Mannich base by-product generates route
In the etherification reaction of above-mentioned route, be required to carry out under basic conditions, it is reported in the literature there are mainly two types of, one
Kind is using organic alkali, such as potassium tert-butoxide, sodium methoxide；One kind is such as to use solid NaOH or KOH using inorganic strong alkali
Deng.
Chinese patent CN201210329697.8 is original with (E) -3- (N- methylamino) -1- phenyl -2- propylene -1- ketone
Material generates atomoxetine by reduction, with 2- benzyl halide etherification reaction, but starting material 1- phenyl propyne ketone is through retrieving
It was found that source is not easy to obtain without commercial product, there are certain difficulty for industrialization；Pd-C/H is used simultaneously2、Pd(OH)2-C/H2、
Raney Ni/H2The reduction of hydrogen high pressure is carried out to unsaturated double-bond as catalyst, there are high risks for safety operation.
U.S.Pat.No.6541668 reports one kind with 1,3 dimethyl-2-imidazolinones or N-Methyl pyrrolidone
It for solvent, is etherified under the action of organic base, used solvent has stronger toxicity (1,3 dimethyl-2-imidazolinone
There is dermal toxicity with genotoxicity, N-Methyl pyrrolidone), and the reaction time compared with long, step number is more for operation, solvent usage compared with
Greatly.
Zhejiang Ocean college journal (natural science edition), 2017,36 (06): 546-550；Hebei University of Science and Technology's journal,
2008,29 (4): 328-331 carries out heterogeneous reaction using inorganic strong alkali and 3- methylamino -1- phenyl propanol, with non-proton pole
Property solvent DMF be reaction dissolvent, in order to promote negative oxygen ion increasing concentrations, increase its exposed degree, use and Crown properties
Similar PEG-6000 shortens the reaction time as catalyst, improves reaction yield, achieves better effects, raceme
Total recovery has reached 75%, but since pyroreaction, used solvent DMF or DMAc are easy to the N-H with methylamine phenylpropanol
Displacement reaction (Org.Process Res.Dev.2014,18,875-885) occurs, generates amidate impurity, structural formula is as follows
It is shown:
(R=H or CH3)。
U.S.Pat.No.7317127B2 uses aprotic polar solvent dimethyl sulfoxide for etherification reaction solvent, still
DMSO has certain toxicity, has permeability, to the irritating effect of eye to human skin, and the reaction needs long-time high temperature
(145-147 DEG C) is reacted, and DMSO can decompose at 120 DEG C or more in reaction kettle, generates toxic gas, there is dizziness, gas
Taste is very unpleasant.
Summary of the invention
For many shortcomings of the existing technology, the present invention provides a kind of R- (-)-levels Moses spits of fland
With the alcoholic solution of methylamine Aza- occurs for preparation method using 1- phenyl -2- acrylic -1- ketone cheap and easy to get as starting material
Michael reaction terminates that reducing agent sodium borohydride is added portionwise in liquid in reaction, and 3- methylamino -1- has been prepared in one kettle way
Phenyl-1-propanol, then under hypotoxicity, higher boiling solvent, using toluene as azeotropic agent, under inorganic base environment with adjacent toluene halide
Etherificate, through L- mandelic acid (L- (+)-mandelic acid) resolution at salt (R- (-)-atomoxetine-S- (+)-mandelate), essence
It makes, turn hydrochloride and obtain R- (-)-levels Moses spit of fland finished product.Method of the invention eliminates intermediate one step of oxalic acid salt refining,
Reduce reaction step, with supplementary material is cheap and easy to get, side reaction is few, action solvent toxicity is low, high income, purity is high, cost
Low advantage is suitble to industrialization production.
Specifically, shown in technical scheme is as follows:
The present invention provides a kind of R- (-)-levels Moses spit of fland preparation methods, and method of the invention is with compound 1
I.e. 1- phenyl -2- acrylic -1- ketone is that compound 2 i.e. 3- methylamino -1- phenyl-1-propanol is prepared in starting material, then
3- methylamino -1- phenyl-1-propanol is that adjacent toluene halide is etherified with compound 3 under inorganic base environment, is torn open through L- (+)-mandelic acid
Get compound 4 i.e. R- (-)-atomoxetine-S- (+)-mandelate and then purification R- (-)-atomoxetine-S- (+)-is flat
Peach hydrochlorate turns hydrochloride up to R- (-)-levels Moses spit of fland.
In embodiments of the present invention, described to prepare 3- methylamine by starting material of 1- phenyl -2- acrylic -1- ketone
The step of base -1- phenyl-1-propanol (one kettle way) includes: the alcoholic solution generation Aza- of 1- phenyl -2- acrylic -1- ketone and methylamine
Sodium borohydride is added portionwise when no 1- phenyl -2- acrylic -1- ketone residual in Michael addition reaction, controls reaction temperature,
Up to 3- methylamino -1- phenyl-1-propanol.
In certain embodiments of the present invention, the 3- methylamino -1- phenyl-1-propanol is related to the step of purifying, than
Can such as be added purified water and hydrochloric acid in the reaction system after the completion of reaction, the volume ratio of purified water and hydrochloric acid be 5:1 (such as
The hydrochloric acid of 10L purified water and 2L 2N), after stirring 20-40min, extractant such as toluene is added and is extracted, extraction can carry out
1 to repeatedly such as 2 times, after merging organic phase, washed using purified water to get 3- methylamino -1- phenyl-1-propanol solution.
In embodiments of the present invention, it is described be added portionwise it is i.e. non-disposable it is whole be added, for example can divide 2 at most
Secondary addition, adding manner can for every time equal portions perhaps gradually progressively increase the time interval that is added every time can it is identical or by
It is tapered short.
In certain embodiments of the present invention, the alcoholic solution of the methylamine is the ethanol solution of methylamine or the methanol of methylamine
Solution.In yet other embodiments, the alcoholic solution of the methylamine is that the ethyl alcohol for the methylamine that concentration is 33% (mass concentration) is molten
Liquid.
In certain embodiments of the present invention, the temperature of the Aza-Michael addition reaction is 20-40 DEG C, again
In some embodiments, which is 25-30 DEG C.
In certain embodiments of the present invention, the alcoholic solution of the methylamine and 1- phenyl -2- acrylic -1- ketone rub
You are than being 1.0-1.5:1；In yet other embodiments, which is 1.2-1.4:1.
In certain embodiments of the present invention, sodium borohydride is added portionwise, control reaction temperature is -5-5 DEG C；Again
In some embodiments, control reaction temperature is -2~2 DEG C, for example the temperature may be controlled to -1-1 DEG C, 0-2 DEG C or -2-0
℃。
In certain embodiments of the present invention, 1- phenyl -2- acrylic -1- ketone and the molar ratio of sodium borohydride total amount are
1:1.0-1.2, in yet other embodiments, the molar ratio can be 1:1.0,1:1.05,1:1.08,1:1.2.
In embodiments of the present invention, (i.e. R- (-)-atomoxetine-S- (+)-is flat for the atomoxetine mandelate
Peach hydrochlorate) preparation include: 3- methylamino -1- phenyl-1-propanol and adjacent toluene halide in reaction dissolvent, be to take water with toluene
Agent is etherified in inorganic base environment, is split into salt through mandelate (i.e. L- (+)-mandelic acid) and is obtained R- (-)-atomoxetine-
S- (+)-mandelate.
In certain embodiments of the present invention, the halogen in adjacent toluene halide can be F, Cl, Br etc., more be preferably neighbour
Toluene fluoride.
In certain embodiments of the present invention, 3- methylamino -1- phenyl-1-propanol and the reaction dissolvent of adjacent toluene halide are
Hypotoxicity, higher boiling solvent are selected from glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl
One of ether, dibutyl ethylene glycol ether and triethylene glycol dimethyl ether are a variety of；In yet other embodiments, the reaction dissolvent
For triethylene glycol dimethyl ether.
In certain embodiments of the present invention, above-mentioned to be selected from hypotoxicity, the reaction dissolvent of higher boiling solvent and 3- methylamine
The mass ratio of base -1- phenyl-1-propanol is 1-5:1；In yet other embodiments, which is 2-4:1.
In certain embodiments of the present invention, the molar ratio of adjacent toluene halide and 3- methylamino -1- phenyl-1-propanol is
0.8-4:1；In yet other embodiments, which is 1-3:1.
In certain embodiments of the present invention, the inorganic base is in sodium hydroxide, potassium hydroxide and potassium carbonate
It is one or more；Preferably potassium hydroxide.
In certain embodiments of the present invention, the reaction temperature of the etherificate is 100-140 DEG C；In other embodiment party
In formula, which is 120-130 DEG C.
In certain embodiments of the present invention, mandelate is added to split to obtain R- (-)-atomoxetine-S- (+)-almond
The process of hydrochlorate includes the operation that L- (+)-mandelic acid is added after etherification reaction and carries out high temperature recrystallization, including L- is added
(+)-mandelic acid after being heated with stirring to 75-80 DEG C, is cooled to 65-70 DEG C of addition crystal seed (i.e. pure R- (-)-atomoxetine-S-
(+)-mandelate), it is slowly dropped to room temperature, then 0-5 DEG C of ice-water bath growing the grain, filtered, washed filter cake with cold ethyl acetate and remove
Toluene is removed, R- (-)-atomoxetine-S- (+)-mandelate is obtained.
In embodiments of the present invention, including to R- (-)-atomoxetine-S- (+)-mandelate purification step will
High temperature recrystallizes R- (-)-atomoxetine-S- (+)-mandelate in organic solvent.
In certain embodiments of the present invention, the organic solvent in the subtractive process is ethyl acetate and/or acetic acid
Butyl ester；More it is preferably ethyl acetate.
In certain embodiments of the present invention, organic solvent used in subtractive process and R- (-)-Tuo Mo to be refined
Xi Ting-S- (+)-mandelate mass ratio is 5-10:1；In yet other embodiments, which is 7-9:1.
In certain embodiments of the present invention, the temperature of the high temperature recrystallization is 60-80 DEG C；In certain embodiments
In, which is first to be warming up to 75-80 DEG C, is then cooled to 65-70 DEG C again.
In certain embodiments of the present invention, the step of purification R- (-)-atomoxetine-S- (+)-mandelate
Include: that R- (-)-atomoxetine-S- (+)-mandelate and organic solvent is added, temperature is first warming up to 75-80 DEG C, is then dropped
Temperature is to 65-70 DEG C of addition crystal seed (i.e. pure R- (-)-atomoxetine-S- (+)-mandelate), slow cooling crystallization.Some
In embodiment, slow cooling precipitates crystal growing the grain to 5 DEG C, filters, and with cold that ethyl acetate elutes filter paper, vacuum drying is obtained
The R- (-) of purification-atomoxetine-S- (+)-mandelate.
In embodiments of the present invention, the preparation of described the step of turning hydrochloride i.e. R- (-)-levels Moses spit of fland walks
Suddenly include: purification after R- (-)-atomoxetine-S- (+)-mandelate through alkalization, extraction, drying, be added dropwise concentrated hydrochloric acid at salt i.e.
R- (-)-levels Moses spit of fland crude product is obtained, crude product obtains R- (-)-levels Moses in solvent system high temperature dilution crystallization
Spit of fland.
In certain embodiments of the present invention, it is described turn hydrochloride during, extract the extractant that uses and be selected from second
Acetoacetic ester and/or sec-butyl acetate；More it is preferably sec-butyl acetate.
In certain embodiments of the present invention, the extractant and R- (-)-atomoxetine-S- (+)-mandelate
Mass ratio is 3-7:1；In yet other embodiments, which is 4-6:1.
In certain embodiments of the present invention, above-mentioned solvent system includes good solvent and poor solvent, wherein described good
Solvent is selected from one of methylene chloride, methanol and ethyl alcohol or a variety of；The poor solvent is selected from ethyl acetate and/or acetic acid is secondary
Butyl ester.In yet other embodiments, the solvent system includes methylene chloride and ethyl acetate.
In certain embodiments of the present invention, the mass ratio of the good solvent and R- (-)-levels Moses spit of fland crude product
For 8-12:1；In yet other embodiments, which is 9-11:1.
In certain embodiments of the present invention, the quality of the poor solvent and R- (-)-levels Moses spit of fland crude product
Than for 6-12:1；In yet other embodiments, which is 9-11:1.
In certain embodiments of the present invention, 20-50 DEG C of temperature range of the high temperature dilution crystallization；In other reality
It applies in mode, which is 30-40 DEG C.
In some embodiments of the present invention, the R- (-)-levels Moses spit of fland preparation method includes: with 1-
Phenyl -2- acrylic -1- ketone is the alcoholic solution generation Aza-Michael addition reaction of starting material and methylamine, to no 1- phenyl -
When 2- acrylic -1- ketone remains, sodium borohydride is added portionwise, controls reaction temperature, 3- methylamino -1- phenyl-1-propanol is made；
3- methylamino -1- phenyl-1-propanol obtained and adjacent toluene halide are in reaction dissolvent, using toluene as azeotropic agent, in inorganic base ring
It is etherified in border, obtains R- (-)-atomoxetine-S- (+)-mandelate at salt through L- (+)-mandelic acid resolution；By what is obtained
High temperature recrystallization is refined R- (-)-atomoxetine-S- (+)-mandelate in organic solvent, R- (-)-support after purification
Moses spit of fland-S- (+)-mandelate is through alkalization, extraction, drying, dropwise addition concentrated hydrochloric acid at salt up to R- (-)-levels Moses spit of fland
Crude product, crude product obtain R- (-)-levels Moses spit of fland in solvent system high temperature dilution crystallization.
In some embodiments of the present invention, the R- (-)-levels Moses spit of fland preparation method includes following step
It is rapid:
1- phenyl -2- acrylic -1- ketone is slowly added dropwise in the alcoholic solution of methylamine, control temperature is anti-in 20-40 DEG C of stirring
It answers, when sample detection to no 1- phenyl -2- acrylic -1- ketone remains, sodium borohydride, control system temperature -5-5 is added portionwise
DEG C, the molar ratio of 1- phenyl -2- acrylic -1- ketone and sodium borohydride total amount is 1:1.0-1.2, is added after being stirred to react pure
Toluene extraction 2 is added to multiple, merging organic phase in change water, hydrochloric acid, stirring, and addition purified water washing obtains 3- methylamino -1-
Phenyl -1- propyl alcohol toluene solution.
Under room temperature, hypotoxicity, higher boiling solvent are added into the 3- methylamino -1- phenyl-1-propanol toluene solution
As reaction dissolvent, such as triethylene glycol dimethyl ether, the mass ratio of the reaction dissolvent and 3- methylamino -1- phenyl-1-propanol is
Inorganic base such as potassium hydroxide is added in 1-5:1, and it is 100-140 DEG C that stirring, which is warming up to system temperature, reflux water-dividing, and adjacent halogen is added
The molar ratio of toluene (such as o-fluorotobuene), adjacent toluene halide and 3- methylamino -1- phenyl-1-propanol is 0.8-4:1, HPLC detection
Reaction end.After reaction, stop heating, be cooled to 90 DEG C, purified water, liquid separation are added into system, organic phase is washed with water
It washs, liquid separation, obtains rufous organic layer.Fuel-displaced phase is shifted, L- (+)-mandelic acid is added, is heated with stirring to 75-80 DEG C, then drops
Temperature is slowly dropped to room temperature, then 0- to 65-70 DEG C of addition crystal seed (i.e. pure R- (-)-atomoxetine-S- (+)-mandelate)
5 DEG C of ice-water bath growing the grains filter, and wash filter cake with cold ethyl acetate and remove toluene, obtain white R- (-)-atomoxetine-S-
(+)-mandelate solid.
The R- (-)-atomoxetine-S- (+)-mandelate is taken, is added organic solvent (such as ethyl acetate), stirring heating
To 75-80 DEG C, it is then cooled to 65-70 DEG C of addition crystal seed (i.e. pure R- (-)-atomoxetine-S- (+)-mandelate), slowly
5 DEG C of growing the grains are cooled to, are filtered, with cold that ethyl acetate elutes, 45 DEG C of vacuum drying, R- (-)-atomoxetine-refined
S- (+)-mandelate.
R- (-)-atomoxetine-S- (+)-mandelate of the purification is taken to alkalize, (alkalinization such as can be to add
Enter 40-45 DEG C of sodium hydrate aqueous solution stirring), extractant extraction is added, extractant can be such as sec-butyl acetate, extract
Liquid separation after finishing is washed with water after oily phase after dry filter and washs filter cake using sec-butyl acetate, merges and delays after organic phase under room temperature
Slowly concentrated hydrochloric acid is added dropwise, stirring to crystal is precipitated, and slow cooling to 0-5 DEG C of growing the grain filters, filter cake is eluted with the cold ethyl acetate that obtains,
Vacuum drying obtains R- (-)-levels Moses spit of fland crude product.The R- (-)-levels Moses spit of fland crude product is taken, with good solvent ratio
After methylene chloride dissolution, the mass ratio of good solvent and R- (-)-levels Moses spit of fland crude product is 8-12:1, is slowly heated to
30-40 DEG C, keep temperature-resistant, until poor solvent (such as ethyl acetate) is added, poor solvent and R- (-)-levels
The mass ratio of Moses spit of fland crude product is 6-12:1, after poor solvent is added dropwise, is cooled to room temperature, then cooled down with ice-water bath, 0-5 DEG C
Lower growing the grain filters, washs filter cake with ethyl acetate, is dried in vacuo, obtains R- (-)-levels Moses spit of fland finished product.
Compared to the prior art, present invention has an advantage that the present invention using L- mandelic acid resolution at salt method,
Oxalates subtractive process is eliminated, improves yield while shortening reaction step, total recovery of the invention has reached 35-
37%, it is significantly improved compared to reported in the literature 30% or so.
In addition, the present invention uses 1- phenyl -2- acrylic -1- ketone cheap and easy to get for starting material, using " treating different things alike "
3- methylamino -1- phenyl-1-propanol has been prepared in method, then in higher boiling, the solvent such as triethylene glycol diformazan of hypotoxicity
It is etherified in ether with adjacent toluene halide (such as o-fluorotobuene), L- mandelic acid resolution is added into salt, the step such as refined, turn hydrochloride
Suddenly target product is obtained, preparation method provided by the invention is simple, efficient, with raw material sources are extensive, side reaction is few, yield
High (35-37%), it is at low cost the advantages that, be suitble to industrialization production.
Detailed description of the invention
The accompanying drawings constituting a part of this application is used to provide further understanding of the present application, and the application's shows
Meaning property embodiment and its explanation are not constituted an undue limitation on the present application for explaining the application.Hereinafter, coming in conjunction with attached drawing detailed
Describe bright embodiment of the present invention in detail, in which:
Fig. 1 is the test map in relation to substance I in the product of embodiment 1；It is wherein impurity at 8.8min and 16.3min
B,D；
Fig. 2 is the test map in relation to substance II in the product of embodiment 1.
Specific embodiment
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part or according to the normal condition proposed by manufacturer.
Unless otherwise defined, it anticipates known to all professional and scientific terms as used herein and one skilled in the art
Justice is identical.Reagent or raw material used in the present invention can be bought by conventional route and be obtained, unless otherwise specified, institute of the present invention
The reagent or raw material used is used according to this field usual manner or is used according to product description.In addition, any and institute
The similar or impartial method of contents and material can be applied to the method for the present invention.Preferable implementation method described in the text with
Material is for illustrative purposes only.
In embodiments of the present invention, the R- (-)-levels Moses spit of fland preparation method the following steps are included:
(1) the compound 1 i.e. 1- phenyl -2- acrylic -1- ketone (alcoholic solution of methylamine is slowly added dropwise in the alcoholic solution of methylamine
Molar ratio with 1- phenyl -2- acrylic -1- ketone is 1.0-1.5:1, for example can be 1.2:1,1.3:1 or 1.4:1), control
Temperature is stirred to react, sample detection to no 1- phenyl -2- acrylic -1- ketone 20-40 DEG C (for example can be 25 DEG C or 30 DEG C)
When residual, sodium borohydride is added portionwise, (temperature can be -1-1 DEG C, 0-2 DEG C or -2-0 to -5-5 DEG C of control system temperature
DEG C), the molar ratio of 1- phenyl -2- acrylic -1- ketone and sodium borohydride total amount be 1:1.0-1.2 (molar ratio can be 1:
1.0,1:1.05,1:1.08,1:1.2), purified water, hydrochloric acid are added after being stirred to react, toluene extraction 2 is added at most in stirring
It is secondary, merge organic phase, purified water washing is added, obtains compound 2 i.e. 3- methylamino -1- phenyl-1-propanol toluene solution, to
With.
(2) under room temperature, to 2 solution of compound obtained in step (1), that is, 3- methylamino -1- phenyl-1-propanol first
Hypotoxicity is added in benzole soln, higher boiling solvent is used as reaction dissolvent, such as triethylene glycol dimethyl ether, the reaction dissolvent and 3- first
The mass ratio of amido -1- phenyl-1-propanol is 1-5:1 (such as 1:1,1.5:1,2:1,3:1,4:1 or 5:1), and inorganic base is added
Such as potassium hydroxide, it is 100-140 DEG C (for example the temperature is 120 DEG C, 125 DEG C or 130 DEG C) that stirring, which is warming up to system temperature, is returned
Flow point water, is added adjacent toluene halide (such as o-fluorotobuene), and the molar ratio of adjacent toluene halide and 3- methylamino -1- phenyl-1-propanol is
0.8-4:1 (for example can be 0.8:1,1:1,1.5:1,2:1,3:1 or 4:1), HPLC detect reaction end.After reaction,
Stop heating, is cooled to 90 DEG C, purified water, liquid separation are added into system, organic phase is washed with water, liquid separation, and obtaining rufous has
Machine layer.It shifts fuel-displaced phase, L- (+)-mandelic acid is added, being heated with stirring to 75-80 DEG C, (for example the temperature can be 75 DEG C, 78 DEG C
Or 80 DEG C), it is then cooled to 65-70 DEG C (for example the temperature is 65 DEG C, 66 DEG C, 68 DEG C or 70 DEG C) and crystal seed (i.e. pure R- is added
(-)-atomoxetine-S- (+)-mandelate), it is slowly dropped to room temperature, then 0-5 DEG C of ice-water bath growing the grain, filtered, with cold acetic acid
Ethyl ester washs filter cake and removes toluene, obtains white R- (-)-atomoxetine-S- (+)-mandelate solid.
(3) R- (-)-atomoxetine-S- (+)-mandelate is taken, is added organic solvent (such as ethyl acetate), stirring
It is warming up to 75-80 DEG C (such as the temperature can for 75 DEG C, 78 DEG C or 80 DEG C), being then cooled to 65-70 DEG C, (for example the temperature is
65 DEG C, 66 DEG C, 68 DEG C or 70 DEG C) crystal seed (i.e. pure R- (-)-atomoxetine-S- (+)-mandelate) is added, slow cooling is extremely
5 DEG C of growing the grains filter, with cold that ethyl acetate elutes, 45 DEG C of vacuum drying, the R- (-) refined-atomoxetine-S- (+)-
Mandelate.
(4) R- (-)-atomoxetine-S- (+)-mandelate of the purification is taken to alkalize, (alkalinization such as can be with
For 40-45 DEG C of sodium hydrate aqueous solution stirring is added), extractant extraction is added, extractant such as can be sec-butyl acetate, extraction
Liquid separation after taking is washed with water after oily phase after dry filter and washs filter cake using sec-butyl acetate, merges room temperature after organic phase
Under be slowly added dropwise concentrated hydrochloric acid, stirring to crystal is precipitated, slow cooling to 0-5 DEG C of growing the grain, filters, with cold ethyl acetate elution filter
Cake, vacuum drying obtain R- (-)-levels Moses spit of fland crude product.The R- (-)-levels Moses spit of fland crude product is taken, good solvent is used
Such as after methylene chloride dissolution, the mass ratio of good solvent and R- (-)-levels Moses spit of fland crude product is 8-12:1 (mass ratio
For example be 9:1,10:1 or 11:1), it is slowly heated to 30-40 DEG C (such as 30 DEG C, 35 DEG C or 40 DEG C), keeps temperature-resistant, directly
To poor solvent (such as ethyl acetate) is added, the mass ratio of poor solvent and R- (-)-levels Moses spit of fland crude product is 6-
12:1 (for example the mass ratio is 7.2:1,8:1 or 8.8:1), after poor solvent is added dropwise, is cooled to room temperature, then use ice-water bath
Cooling, growing the grain at 0-5 DEG C filter, washs filter cake with ethyl acetate, vacuum drying, obtain R- (-)-levels Moses spit of fland at
Product.
In order to which technical solution of the present invention, the specific example of preparation provided below is preferably presented.
Crystal seed R- (-) of the present invention-atomoxetine-S- (+)-mandelate the preparation method is as follows:
33% methylethylolamine solution 1.36kg is added in reaction kettle, 1- phenyl -2- propylene is slowly added dropwise under stirring
Base -1- ketone 1.58kg, 25 DEG C of temperature control are stirred to react, and when sample detection supplementary material noresidue, sodium borohydride 0.48kg is added portionwise,
- 1~1 DEG C of control system temperature, purified water 10L, 2L 2N hydrochloric acid is added after being stirred to react, after stirring 30min, is added
10L toluene is extracted twice, and merges organic phase, and the washing of 20L purified water obtains 3- methylamino -1- phenyl-1-propanol toluene solution, to
With.
Under room temperature, three second are added into the above-mentioned reaction kettle equipped with 3- methylamino -1- phenyl-1-propanol toluene solution
Reaction kettle is added in glycol dimethyl ether 4.4kg, KOH 2.39kg, and stirring is warming up to system temperature to 120 DEG C, and reflux water-dividing 1h adds
Enter o-fluorotobuene 1.32kg, react about 3h, HPLC detects reaction end.After reaction, stop heating, be cooled to 90 DEG C,
Purified water 10kg, liquid separation are added into system, organic phase obtains rufous organic layer with 10kg water washing 2 times, liquid separation.Transfer
It is oily L- (+)-mandelic acid 1.10kg to be added, is heated with stirring to 75 DEG C, is then slowly dropped to room temperature mutually into reaction kettle, then 0~
5 DEG C of ice-water bath growing the grain 1h are filtered, and are washed filter cake with cold ethyl acetate and are removed toluene therein, and white R- (-)-support Moses is obtained
Spit of fland-S- (+)-mandelate crude product.
Mandelate crude product 1.8kg and ethyl acetate 12.6kg is added into reaction kettle, stirring is warming up to 75 DEG C, then
5 DEG C of growing the grain 1h are slowly dropped to, are filtered, elute filter with cold ethyl acetate, 45 DEG C of vacuum drying 3h or more obtain R- (-)-Tuo Mo
Xi Ting-S- (+)-mandelate is detected according to the detection method in test example in relation to substance, and each impurity is not greater than
0.1%, principal component purity is greater than 99.9%, if unqualified, repeats purification according to above-mentioned purification method to get crystal seed R- (-)-
Atomoxetine-S- (+)-mandelate.
Embodiment 1
33% methylethylolamine solution 1.36kg is added in reaction kettle, 1- phenyl -2- propylene is slowly added dropwise under stirring
Base -1- ketone 1.58kg, 25 DEG C of temperature control are stirred to react, and when sample detection supplementary material noresidue, sodium borohydride 0.48kg is added portionwise,
- 1~1 DEG C of control system temperature, purified water 10L, 2L 2N hydrochloric acid is added after being stirred to react, after stirring 30min, is added
10L toluene is extracted twice, and merges organic phase, and the washing of 20L purified water obtains 3- methylamino -1- phenyl-1-propanol toluene solution, to
With.
Under room temperature, three second are added into the above-mentioned reaction kettle equipped with 3- methylamino -1- phenyl-1-propanol toluene solution
Reaction kettle is added in glycol dimethyl ether 4.4kg, KOH 2.39kg, and stirring is warming up to system temperature to 120 DEG C, and reflux water-dividing 1h adds
Enter o-fluorotobuene 1.32kg, react about 3h, HPLC detects reaction end.After reaction, stop heating, be cooled to 90 DEG C,
Purified water 10kg, liquid separation are added into system, organic phase obtains rufous organic layer with 10kg water washing 2 times, liquid separation.Transfer
Oily phase is added L- (+)-mandelic acid 1.10kg, is heated with stirring to 75 DEG C, 65 DEG C of addition crystal seed (purified supports into reaction kettle
Moses spit of fland mandelate), it is slowly dropped to room temperature, then 0~5 DEG C of ice-water bath growing the grain 1h, filters, wash filter with cold ethyl acetate
Cake removes toluene therein, obtains white R- (-)-atomoxetine-S- (+)-mandelate solid, yield: 42%.
Mandelate 1.8kg and ethyl acetate 12.6kg is added into reaction kettle, stirring is warming up to 75 DEG C, is then down to 65
DEG C, it is added crystal seed (purified atomoxetine mandelate), is slowly dropped to 5 DEG C of growing the grain 1h, filter, drenched with cold ethyl acetate
Filter wash, 45 DEG C of vacuum drying 3h or more, obtains R- (-)-atomoxetine-S- (+)-mandelate fine work, yield: 93%.
Addition 1.62kg R- (-)-atomoxetine-S- (+)-mandelate into reaction kettle, (7 times of 11.34kg purified water
Volume mass ratio), then 0.24kgNaOH is dissolved with 1.62kg water, it is added into reaction kettle, 40~45 DEG C are stirred 10 minutes,
6.48kg sec-butyl acetate, liquid separation is added, oil is mutually purified with 2kg respectively to be washed 3 times, shifts oil mutually to reaction kettle, 0.9kg is added
Anhydrous magnesium sulfate stirs dry 30min, filters, washs filter cake twice with 1kg sec-butyl acetate respectively, merges organic phase, is transferred to
In reaction kettle, concentrated hydrochloric acid is slowly added dropwise under room temperature, is added dropwise in 1h, stirring to crystal is precipitated, and slow cooling cools to 0 DEG C
~5 DEG C growing the grain 1 hour, filter, with cold ethyl acetate elute filter cake 2 times, 50 DEG C of vacuum drying 3h obtain white R- (-)-hydrochloric acid
Atomoxetine crude product, yield: 94%.
The above-mentioned crude product of 1.05kg is added into reaction kettle, is dissolved with 9.45kg methylene chloride, is slowly heated 30 DEG C, keeps
It is temperature-resistant, it is directly added into ethyl acetate 1.89kg, is added crystal seed (purified R- (-)-levels Moses spit of fland), then
7.56kg ethyl acetate is slowly added dropwise, is added dropwise in 2h, after being added dropwise, is cooled to room temperature, then cooled down with ice-water bath, 0
Growing the grain 1h at~5 DEG C filters, washs filter cake twice with ethyl acetate, 50 DEG C of vacuum drying 3h obtain R- (-)-levels not
Western spit of fland finished product, yield: 95%.
Embodiment 2
33% methylethylolamine solution 1.36kg is added in reaction kettle, 1- phenyl -2- propylene is slowly added dropwise under stirring
Base -1- ketone 1.58kg, 25 DEG C of temperature control are stirred to react, and when sample detection supplementary material noresidue, sodium borohydride 0.49kg is added portionwise,
Purified water 10L, 2L 2N hydrochloric acid is added in 0-2 DEG C of control system temperature after being stirred to react, after stirring 30min, 15L is added
Toluene is extracted twice, and merges organic phase, and the washing of 20L purified water obtains 3- methylamino -1- phenyl-1-propanol toluene solution, for use.
Under room temperature, three second are added into the above-mentioned reaction kettle equipped with 3- methylamino -1- phenyl-1-propanol toluene solution
Reaction kettle is added in glycol dimethyl ether 6.6kg, KOH 2.39kg, and stirring is warming up to system temperature to 125 DEG C, and reflux water-dividing 1h adds
Enter o-fluorotobuene 2.6kg, react about 2h, HPLC detects reaction end.After reaction, stop heating, be cooled to 90 DEG C, to
Purified water 10kg, liquid separation are added in system, organic phase obtains rufous organic layer with 10kg water washing 2 times, liquid separation.Transfer oil
Mutually into reaction kettle, L- (+)-mandelic acid 1.10kg being added, is heated with stirring to 78 DEG C, 66 DEG C of addition crystal seeds are slowly dropped to room temperature,
Then 0~5 DEG C of ice-water bath growing the grain 1h is filtered, and is washed filter cake with cold ethyl acetate and is removed toluene therein, obtains white R- (-)-
Atomoxetine-S- (+)-mandelate solid, yield: 44%.
Mandelate 1.8kg and ethyl acetate 14.4kg is added into reaction kettle, stirring is warming up to 78 DEG C, is then down to 68
DEG C, it is added crystal seed (purified atomoxetine mandelate), is slowly dropped to 5 DEG C of growing the grain 1h, filter, drenched with cold ethyl acetate
Filter wash cake, 45 DEG C of vacuum drying 3h or more, obtains R- (-)-atomoxetine-S- (+)-mandelate fine work, yield: 92%.
Addition 1.62kg R- (-)-atomoxetine-S- (+)-mandelate into reaction kettle, (7 times of 11.34kg purified water
Volume mass ratio), then 0.24kgNaOH is dissolved with 1.62kg water, it is added into reaction kettle, 40~45 DEG C are stirred 10 minutes,
8.1kg sec-butyl acetate, liquid separation is added, oil is mutually purified with 2kg respectively to be washed 3 times, shifts oil mutually to reaction kettle, 0.9kg is added
Anhydrous magnesium sulfate stirs dry 30min, filters, washs filter cake twice with 1.25kg sec-butyl acetate respectively, merges organic phase, turns
Enter in reaction kettle, concentrated hydrochloric acid is slowly added dropwise under room temperature, is added dropwise in 1h, stirring to crystal is precipitated, and slow cooling cools to 0
DEG C~5 DEG C growing the grain 1 hour, filter, with cold ethyl acetate elute filter cake 2 times, 50 DEG C of vacuum drying 3h obtain white R- (-)-
Levels Moses spit of fland crude product, yield: 92%.
The above-mentioned crude product of 1.05kg is added into reaction kettle, is dissolved with 10.5kg methylene chloride, is slowly heated 35 DEG C, keeps
It is temperature-resistant, it is directly added into ethyl acetate 2.1kg, is added crystal seed (purified R- (-)-levels Moses spit of fland), then delays
It is slow that 8.4kg ethyl acetate is added dropwise, it is added dropwise in 2h, is cooled to room temperature, then cooled down with ice-water bath, growing the grain 1h at 0~5 DEG C takes out
Filter, washs filter cake twice with ethyl acetate.50 DEG C of vacuum drying 3h obtain R- (-)-levels Moses spit of fland finished product, yield:
96%.
Embodiment 3
33% methylethylolamine solution 1.36kg is added in reaction kettle, 1- phenyl -2- propylene is slowly added dropwise under stirring
Base -1- ketone 1.58kg, 25 DEG C of temperature control are stirred to react, and when sample detection supplementary material noresidue, sodium borohydride 0.49kg is added portionwise,
- 2~0 DEG C of control system temperature, purified water 10L, 2L 2N hydrochloric acid is added after being stirred to react, after stirring 30min, is added
20L toluene is extracted twice, and merges organic phase, and the washing of 40L purified water obtains 3- methylamino -1- phenyl-1-propanol toluene solution, to
With.
Under room temperature, three second are added into the above-mentioned reaction kettle equipped with 3- methylamino -1- phenyl-1-propanol toluene solution
Reaction kettle is added in glycol dimethyl ether 8.8kg, KOH 2.39kg, and stirring is warming up to system temperature to 130 DEG C, and reflux water-dividing 1h adds
Enter o-fluorotobuene 6.66kg, react about 1.5h, HPLC detects reaction end.After reaction, stop heating, be cooled to 90
DEG C, purified water 10kg, liquid separation are added into system, organic phase obtains rufous organic layer with 10kg water washing 2 times, liquid separation.Turn
Oil is moved mutually into reaction kettle, addition L- (+)-mandelic acid 1.10kg is heated with stirring to 80 DEG C, 70 DEG C of addition crystal seeds are (purified
Atomoxetine mandelate), it is slowly dropped to room temperature, then 0~5 DEG C of ice-water bath growing the grain 1h, filters, washed with cold ethyl acetate
Filter cake removes toluene therein, obtains white R- (-)-atomoxetine-S- (+)-mandelate solid, yield: 45%.
Mandelate 1.8kg and ethyl acetate 16.2kg is added into reaction kettle, stirring is warming up to 80 DEG C, is then down to 70
DEG C, it is added crystal seed (purified atomoxetine mandelate), is slowly dropped to 5 DEG C of growing the grain 1h, filter, drenched with cold ethyl acetate
Filter wash cake, 45 DEG C of vacuum drying 3h or more, obtains R- (-)-atomoxetine-S- (+)-mandelate fine work, yield: 92%.
Addition 1.62kg R- (-)-atomoxetine-S- (+)-mandelate into reaction kettle, (7 times of 11.34kg purified water
Volume mass ratio), then 0.24kgNaOH is dissolved with 1.62kg water, it is added into reaction kettle, 40~45 DEG C are stirred 10 minutes,
9.72kg sec-butyl acetate, liquid separation is added, oil is mutually purified with 2kg respectively to be washed 3 times, shifts oil mutually to reaction kettle, 0.9kg is added
Anhydrous magnesium sulfate stirs dry 30min, filters, washs filter cake twice with 1kg sec-butyl acetate respectively, merges organic phase, is transferred to
In reaction kettle, concentrated hydrochloric acid is slowly added dropwise under room temperature, is added dropwise in 1h, stirring to crystal is precipitated, and slow cooling cools to 0 DEG C
~5 DEG C growing the grain 1 hour, filter, with cold ethyl acetate elute filter cake 2 times, 50 DEG C of vacuum drying 3h obtain white R- (-)-salt
Sour atomoxetine crude product, yield: 91%.
The above-mentioned crude product of 1.05kg is added into reaction kettle, is dissolved with 11.55kg methylene chloride, is slowly heated 40 DEG C, keeps
It is temperature-resistant, it is directly added into ethyl acetate 2.31kg, is added crystal seed (purified R- (-)-levels Moses spit of fland), then
9.24kg ethyl acetate is slowly added dropwise, is added dropwise in 2h, after being added dropwise, is cooled to room temperature, then cooled down with ice-water bath, 0
Growing the grain 1h at~5 DEG C filters, washs filter cake twice with ethyl acetate.50 DEG C of vacuum drying 3h, obtain R- (-)-levels not
Western spit of fland finished product, yield: 94%.
Comparative example
Comparative example is referring to institute in Fan Zhen tomoxetine hydrochloride bulk pharmaceutical chemicals preparation process and scale-up research [D] 2015.
Method progress is stated, detailed process is as follows:
3- methylamino -1- phenylpropanol 20g is dissolved in 100mL methylene chloride, addition 28.8g di-tert-butyl dicarbonate, 35
It DEG C is stirred to react 1 hour.Methylene chloride is evaporated off, the dissolution of 300ml toluene is added, sequentially adds 23.0g diethyl azodiformate,
14.3g o-fluorotobuene, is slowly added to 43.6g triphenylphosphine, is stirred to react at room temperature for 24 hours, has a large amount of white powders to generate, and stops
Reaction, filters to obtain white powder solid and pale yellow solution, filtered solution is washed twice with sodium carbonate liquor, dilute hydrochloric acid solution
It washes twice, n-hexane washs three times, and saturated common salt is washed one time, and anhydrous sodium sulfate is dry, and concentration is cooling that white crystal is precipitated
35.4g, yield 83.6%.
It takes the product 15g of back to be placed in 100mL round-bottomed flask, water 50mL is added, is adjusted to pH with sodium carbonate liquor
8-9, dimethylbenzene extract (30mL × 3), are washed (15mL × 2) in dimethylbenzene extracting solution with saturated sodium-chloride, and anhydrous magnesium sulfate is dry
It is dry, it filters, the dimethylbenzene for containing L (+) mandelic acid is added in filtrate, 3h is stirred at room temperature, rear that ether precipitation solid is added, filtering is washed
It washs, it is dry to crystallize 9.3g, yield 38.8% to get white (+)-[R- atomoxetine-S-MA salt].
(+)-[R- atomoxetine-S-MA salt] crystallization 8g is put into 100mL reaction flask, adds water 30mL, uses NaOH
Solid adjusts pH to 9, and ether extracts (30mL × 3), combining extraction liquid, with saturated common salt water washing (15mL × 3), anhydrous slufuric acid
Magnesium dries, filters, and 30% HCl- diethyl ether solution is added in ether filtrate, adjusts pH to 2~3 and puts at a temperature of 0~5 DEG C
1h is set, white solid is collected；With methylene chloride and re-crystallizing in ethyl acetate, vacuum drying obtains white hydrochloride atomoxetine finished product
4.8g, yield 84.0%.
Test example
Known R- (-)-levels Moses spit of fland major impurity is A-E, and chemical name and structural formula are as follows:
In relation to substance I: impurity A, the testing conditions of impurity E and method
Chromatographic column: C18 column, 250mm × 4.6mm, 5 μm of partial size
Detection wavelength: 210nm
Column temperature: 30 DEG C
Flow velocity: 1ml/min
Sampling volume: 20 μ l
Runing time: 55min
Buffer solution: preparing the biphosphate sodium water solution of 12.8g/L, and into the above-mentioned solution of 1L, 4.3g is added
Octyl sodium sulfonate is filtered with phosphorus acid for adjusting pH to 2.8, is ultrasonic, to obtain the final product.
Mobile phase A: acetonitrile: buffer=3:5
Mobile phase B: acetonitrile: methanol: buffer=8:5:6
Dissolve phase: mobile phase A: Mobile phase B=3:1
Type of elution: gradient elution
Table 1 is in relation to I analysis method gradient elution program of substance
| 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 suitability test solution: tomoxetine hydrochloride sample and impurity A, impurity D, appropriate impurity E are mutually made every with dissolution
Mixed solution (limit that the amount of impurity the is respectively each impurity) conduct of 1ml containing about 1.0mg tomoxetine hydrochloride and its each impurity
System suitability solution.
Test solution: weighing tomoxetine hydrochloride test sample about 10mg, accurately weighed, sets in 10ml measuring bottle, solubilization solution
Phase dilution dissolves and is settled to scale.
Contrast solution: precision draws test solution 0.5ml, sets in 50ml volumetric flask, solubilization solution phase dilution dissolves and determines
Hold to scale；Precision pipettes above-mentioned solution 1.0ml again, sets in 10ml volumetric flask, and solubilization solution phase dilution dissolves and be settled to scale,
To obtain the final product.
System suitability takes dissolution mutually and each 20 μ l sample introduction of above system applicability test solution, is injected separately into liquid chromatogram
Instrument；Separating degree R >=1.5 of main peak and adjacent peak (impurity D), separating degree R >=1.5 between impurity A peak and impurity E peak, main peak
Theoretical cam curve N >=3000, main peak tailing factor T≤2.0.
Measuring method: test solution and each 20 μ l injection liquid chromatograph of contrast solution are taken respectively, records chromatogram；It deducts
Blank solvent and impurity D chromatographic peak, impurity A, impurity E are not greater than 1.0 times (0.10%) of contrast solution main peak area；Its
His single impurity peak area is not greater than 1.0 times (0.10%) of contrast solution main peak area；Peak area after each impurity correction
With 5 times (0.50%) for being not greater than contrast solution main peak area.
In above-mentioned formula:
Fi: the relative response factor of impurity A, impurity E；
Ai: the peak area of impurity A, impurity E in test solution；
AComparison liquid: main peak peak area in contrast solution；
AOther are total miscellaneous: after blank solvent, impurity A, impurity D, impurity E, the sum of all impurity peak areas.
In relation to substance II: impurity B, the testing conditions of C, D, S- isomers and method
Chromatographic column: 5 μm of partial size of CHIRALCEL AD-H 4.6mm*250mmL
Detection wavelength: 273nm
Column temperature: 25 DEG C
Sample volume: 20 μ l
Flow velocity: 1.0ml/min
Mobile phase: n-hexane: normal propyl alcohol: dehydrated alcohol: diethylamine=95:3:2:0.3
Dissolve phase: dehydrated alcohol: n-hexane=28:72
It is appropriate to weigh impurity B, impurity C, impurity D, S- isomers working reference substance for precision respectively, with dissolution phased soln and dilute
Release be made in every 1ml containing about impurity B, impurity C, impurity D respectively be about 20 μ g, S- isomers amount be about 30 μ g impurity control
Product mixed solution.
Tomoxetine hydrochloride test sample about 20mg is taken, it is accurately weighed, it sets in 10ml measuring bottle, precision draws reference substance stock solution
1ml uses dissolution phased soln to dilute and be settled to scale as system suitability solution into same measuring bottle.
Tomoxetine hydrochloride test sample about 20mg is taken, it is accurately weighed, until being diluted and being determined with dissolution phased soln in 10ml measuring bottle
Hold to scale as test solution.
Precision draws test solution 0.5ml, sets in 50ml volumetric flask, solubilization solution phase dilution dissolves and is settled to scale；
Precision pipettes above-mentioned solution 1.0ml again, sets in 10ml volumetric flask, and solubilization solution phase dilution dissolves and is settled to scale to get control
Solution.
System suitability takes dissolution mutually and each 20 μ l sample introduction of above system applicability test solution, is injected separately into liquid chromatogram
Instrument；Separating degree R >=1.5 of main peak and adjacent peak (S- isomers), main peak tailing factor T≤2.0.
Measuring method: test solution and each 20 μ l injection liquid chromatograph of contrast solution are taken respectively, records chromatogram；It deducts
Blank solvent chromatographic peak, impurity B, impurity C are not greater than 1.0 times (0.1%) of contrast solution main peak area；Impurity D, S- are different
Structure body is not greater than 1.0 times (0.10%) of contrast solution main peak area, 1.5 times (0.15%) respectively.
In above-mentioned formula:
Fi: the relative response factor of impurity B, impurity C, impurity D, S- isomers, respectively 1.18,1.22,1.0,1.0；
Ai: the peak area of matter B, impurity C, impurity D, S- isomers in test solution；
AComparison liquid: main peak peak area in contrast solution.
According to above-mentioned detection method and condition to the R- (-) being prepared in embodiment 1-3 and comparative example-hydrochloric acid Ah
Atomoxetine finished product is detected, as a result as follows:
2 R- (-) of the table-related substance testing result in levels Moses spit of fland
Wherein, the related substance I of finished product and test map in relation to substance II are as depicted in figs. 1 and 2 in embodiment 1.
From table 2 it can be seen that embodiment 1-3 and comparative example are without obvious poor for related substance I (impurity A and impurity E)
It is different, but for related substance II (impurity B, C, D), comparative example detected impurity compared with embodiment 1-3 in comparative example
C, and the amount of impurity B, D are also above embodiment 1-3；For positive testing result, according to above-mentioned detection method, the yield of comparative example
It is almost the same with yield reported in the literature about 30%, purity 99.85% for 27.2%, purity 99.69%；Come from yield
It sees, preparation method total recovery of the invention improves 7-9% or so than comparative example, effectively reduces production cost, whole with bright
Aobvious advantage.
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, although referring to aforementioned reality
Applying example, invention is explained in detail, for those skilled in the art, still can be to aforementioned each implementation
Technical solution documented by example is modified or equivalent replacement of some of the technical features.It is all in essence of the invention
Within mind and principle, any modification, equivalent replacement, improvement and so on be should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of R- (-)-levels Moses spit of fland preparation method, which is characterized in that be with 1- phenyl -2- acrylic -1- ketone
3- methylamino -1- phenyl-1-propanol is prepared in starting material, and then 3- methylamino -1- phenyl-1-propanol is in inorganic base environment
It is lower to be etherified with adjacent toluene halide, it splits to obtain R- (-)-atomoxetine-S- (+)-mandelate through L- (+)-mandelic acid, then refine
R- (-)-atomoxetine-S- (+)-mandelate, turn hydrochloride up to R- (-)-levels Moses spit of fland.
2. preparation method according to claim 1, which is characterized in that the preparation of the 3- methylamino -1- phenyl-1-propanol
It include: the alcoholic solution generation Aza-Michael addition reaction of 1- phenyl -2- acrylic -1- ketone and methylamine, to no 1- phenyl -2-
When acrylic -1- ketone remains, sodium borohydride is added portionwise, controls reaction temperature to get 3- methylamino -1- phenyl-1-propanol.
3. preparation method according to claim 2, which is characterized in that the alcoholic solution of the methylamine is the ethanol solution of methylamine
Or the methanol solution of methylamine；
Preferably, the temperature of the Aza-Michael addition reaction is 20-40 DEG C；
Preferably, the molar ratio of the alcoholic solution of methylamine and 1- phenyl -2- acrylic -1- ketone is 1.0-1.5:1；
Preferably, sodium borohydride is added portionwise, control reaction temperature is -5-5 DEG C；
Preferably, the molar ratio of 1- phenyl -2- acrylic -1- ketone and sodium borohydride total amount is 1:1.0-1.2.
4. preparation method according to claim 1, which is characterized in that the R- (-)-atomoxetine-S- (+)-mandelic acid
The preparation of salt includes: 3- methylamino -1- phenyl-1-propanol and adjacent toluene halide in reaction dissolvent, using toluene as azeotropic agent, in nothing
It is etherified in machine alkali environment, obtains R- (-)-atomoxetine-S- (+)-mandelate at salt through L- (+)-mandelic acid resolution.
5. according to the method described in claim 4, it is characterized in that, the reaction dissolvent be hypotoxicity, higher boiling solvent, be selected from
Glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, dibutyl ethylene glycol ether and three second
One of glycol dimethyl ether is a variety of；
Preferably, the mass ratio of the reaction dissolvent and 3- methylamino -1- phenyl-1-propanol is 1-5:1；
Preferably, the molar ratio of adjacent toluene halide and 3- methylamino -1- phenyl-1-propanol is 0.8-4:1；
Preferably, the inorganic base is selected from one of sodium hydroxide, potassium hydroxide and potassium carbonate or a variety of；
Preferably, the reaction temperature of the etherificate is 100-140 DEG C.
6. preparation method according to claim 1, which is characterized in that the purification R- (-)-atomoxetine-S- (+)-is flat
The step of peach hydrochlorate includes that high temperature recrystallizes in organic solvent by R- (-)-atomoxetine-S- (+)-mandelate.
7. preparation method according to claim 6, which is characterized in that the organic solvent in the subtractive process is acetic acid second
Ester and/or butyl acetate；
Preferably, organic solvent and R- (-)-atomoxetine-S- (+)-mandelate mass ratio are 5~10 in subtractive process:
1；
Preferably, the temperature of the high temperature recrystallization is 60-80 DEG C；
Preferably, the step of purification R- (-)-atomoxetine-S- (+)-mandelate includes: that R- (-)-support Moses is added
Spit of fland-S- (+)-mandelate and organic solvent, are first warming up to 75-80 DEG C for temperature, are then cooled to 65-70 DEG C of addition crystal seed,
Slow cooling crystallization.
8. preparation method according to claim 1, which is characterized in that described the step of turning hydrochloride includes: after refining
R- (-)-atomoxetine-S- (+)-mandelate is through alkalization, extraction, drying, dropwise addition concentrated hydrochloric acid at salt up to R- (-)-hydrochloric acid Ah
Atomoxetine crude product, crude product obtain R- (-)-levels Moses spit of fland in solvent system high temperature dilution crystallization.
9. preparation method according to claim 8, which is characterized in that it is described turn hydrochloride during, extract and use
Extractant is selected from ethyl acetate and/or sec-butyl acetate；
Preferably, the extractant and R- (-)-atomoxetine-S- (+)-mandelate mass ratio are 3-7:1；
Preferably, the solvent system includes good solvent and poor solvent, wherein the good solvent is selected from methylene chloride, methanol
With one of ethyl alcohol or a variety of；The poor solvent is selected from ethyl acetate and/or sec-butyl acetate；
Preferably, the mass ratio of the good solvent and R- (-)-levels Moses spit of fland crude product is 8-12:1；
Preferably, the mass ratio of the poor solvent and R- (-)-levels Moses spit of fland crude product is 6-12:1；
Preferably, 20-50 DEG C of temperature range of the high temperature dilution crystallization.
10. preparation method according to claim 1, which is characterized in that the described method includes: with 1- phenyl -2- acrylic -
1- ketone is the alcoholic solution generation Aza-Michael addition reaction of starting material and methylamine, to no 1- phenyl -2- acrylic -1- ketone
When residual, sodium borohydride is added portionwise, controls reaction temperature, 3- methylamino -1- phenyl-1-propanol is made；3- methylamine obtained
Base -1- phenyl-1-propanol and adjacent toluene halide, using toluene as azeotropic agent, are etherified, through L- in reaction dissolvent in inorganic base environment
(+)-mandelic acid resolution obtains R- (-)-atomoxetine-S- (+)-mandelate at salt；Obtained R- (-)-is held in the palm into Moses
High temperature recrystallization is refined spit of fland-S- (+)-mandelate in organic solvent, the R- (-) after purification-atomoxetine-S- (+)-
Mandelate is through alkalization, extraction, drying, dropwise addition concentrated hydrochloric acid at salt up to R- (-)-levels Moses spit of fland crude product, and crude product is in molten
Media system high temperature dilution crystallization obtains R- (-)-levels Moses spit of fland.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111302958A (en) * | 2020-03-24 | 2020-06-19 | 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 |
| CN113358773A (en) * | 2021-05-21 | 2021-09-07 | 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 |
| KR20240048702A (en) | 2022-10-07 | 2024-04-16 | 씨에스아이엠 주식회사 | Method for preparing 3-methylamino-1-phenyl-1-propanol |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111302958A (en) * | 2020-03-24 | 2020-06-19 | 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 |
| 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 |
| CN113358773A (en) * | 2021-05-21 | 2021-09-07 | 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 |
| KR20240048702A (en) | 2022-10-07 | 2024-04-16 | 씨에스아이엠 주식회사 | Method for preparing 3-methylamino-1-phenyl-1-propanol |
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