CN1946678A - Isolated atomoxetine impurity, processes for the preparation of atomoxetine impurities and their use as reference standards - Google Patents

Abstract

The present invention provides isolated N-methyl-3-(3-methylphenoxy)-3-phenylpropylamine hydrochloride, and preparation thereof as well as of N-methyl-3-(4-methylphenoxy)-3-phenylpropylamine hydrochloride and of N-methyl-3-phenoxy-3-phenylpropylamine hydrochloride. The invention further provides the use of the above compounds as reference markers and/or reference standards during the synthesis of Atomoxetine. Also provided is a method of limiting the amounts of the impurities 3FT (3-fluorotoluene), 4FT (4-fluorotoluene), and FB (fluorobenzene) in the 2-fluorotoluene starting material used in the synthesis of Atomoxetine Hydrochloride. The purity of the Atomoxetine Hydrochloride product is ensured by determining the amounts of 3FT, 4FT, and FB in the 2-fluorotoluene starting material with the marker 3-ATM HCl.

Description

A kind of isolating Tomoxetine hydrochloride impurity, the preparation method of Tomoxetine hydrochloride impurity and as the purposes of reference standard

The cross reference of related application

This applies for 60/583 of claimed 2004.6.28 application; 641; 2004.9.14 the U.S. Provisional Patent Application 60/609 of application; 716,60/622,065 of 2004.10.25 application; 2005.2.11 60/652 of application; 330,60/583,644 of 2004.6.28 application; 2005.2.11 60/652 of application; 332,60/583,643 of 2004.6.28 application; 2005.2.11 60/652 of application; 331,60/666,666 of 2005.3.30 application; 2005.4.26 60/675 of application; 369, the rights and interests of application number the unknown (proxy's tag number 12670/47001) of application number the unknown (proxy's tag number 12670/46803) of 2005.6.9 application and 2005.6.14 application, its full content is attached to herein by reference.

Invention field

The present invention relates to a kind of isolating atomoxetine hcl impurity, the preparation of its preparation and other impurity is with its purposes as reference standard.

Background of invention

Tomoxetine hydrochloride (ATM) is called (R) (-)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine, has following structure:

In addition, the Tomoxetine hydrochloride molecular formula is C ₁₇H ₂₁NO, molecular weight are 255.35, and by 79.96%C, 8.29%H, 5.49%N and 6.27%O weight ratio are formed.The Tomoxetine hydrochloride hydrochloride is an atomoxetine hcl, and commodity are called STRATTERA ^, the prescription oral capsule dosage that is used for the treatment of attention-defective-hyperactivity hyperkinesia obstacle (ADHD) is 10mg, 18mg, 25mg, 40mg and 60mg.EP 0 052 492 open Tomoxetine hydrochlorides are competitive inhibitors of norepinephrine uptake in the mouse hypothalamus synaptosome, effect is respectively than 2 times and 9 times of the racemic mixture of N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine (tomoxetine, " TMX ") and (+)-mapping heights.Tomoxetine hydrochloride is tomoxetine (R)-(-) enantiomorph.

U.S. Patent number 4,018,895 disclose racemic tomoxetine and other aryloxy phenylpropylamine, for example FLUXETINE ^And NISOXETINE ^, the psychiatric treatment effect of these compounds is also disclosed.EP 0 052 492 discloses Tomoxetine hydrochloride, comprises the additive salt that it is pharmaceutically acceptable, and hydrochloride for example also discloses their purposes as thymoleptic.EP 0 721 777 discloses the purposes of Tomoxetine hydrochloride in treatment ADHD.

The manufacture method of atomoxetine hcl known in the art comprises European Patent Publication No EP 0,052 492, U.S. Patent number 4,868,344 and 6,541,668, International Patent Application Publication No. WO 00/58262, and its content is attached to herein by reference.

Known in the art for before the commercialization of a kind of effective pharmaceutical cpd (API) product, setting up the extremely low lower limit of the evaluation of non-characteristic impurity on the toxicology by country and international authority to human body administration security consideration.Usually, limiting the quantity of of every kind of impurity is less than about 0.15% weight ratio.Limiting the quantity of of unidentified and/or non-characteristic impurity is obviously lower, is less than 0.1% weight ratio usually.Therefore, in API makes, before commercialization, require for example purity of atomoxetine hcl of product, identical with the purity of promoting agent in the manufacturing of prescription drug.

Impurity among the API also known in the art may derive from the degraded of API self, and this is related to pure API in the storage and comprises stability in the manufacturing processed of chemosynthesis.Process contaminants comprises chemical derivative, synthetic by product and the degraded product of the impurity that comprises in unreacted raw material, the raw material.

Except the factor of this API of stability in the quality guaranteed period, the purity of the API that produces in the commercial manufacturing process is undoubtedly a business-like prerequisite.The impurity of introducing in the commercial manufacturing process must be limited in seldom amount, and does not preferably exist basically.For example, the ICH Q7A of API manufacturers produces guide and requires in manufacturing processed by clearly stipulating the quality of raw material, control process parameters, for example temperature, pressure, time and stoichiometric ratio, with comprise purification step, for example crystallization, distillation and liquid-liquid extraction keep process contaminants setting below the boundary.

The product mixture of reaction seldom is the simplification compound that the enough purity that meets pharmaceutical standards is arranged.The auxiliary reagent that uses in the byproduct of reaction and by product and the reaction also can appear in the product mixture as a rule.In a certain stage in a kind of API course of processing, whether atomoxetine hcl for example must purity assay, analyzes by HPLC or GC usually, be fit to continue processing and use in medicament production at last to measure it.API does not need definitely pure, because absolute purity is the theory target that is difficult to reach.The purpose of setting up purity rubric is to guarantee API inclusion-free as far as possible, and therefore, clinical use is safe as far as possible.Picture is discussed above, and U.S. food and drug control guilding principle recommend the amount of some impurity to be limited in to be less than 0.1%.

Usually identify byproduct, by product and auxiliary reagent (being generically and collectively referred to as " impurity ") with spectrum and/or other physical method, obtain a peak position then, the spot in the plate of for example peak position in the chromatogram, or TLC.(Strobel p.953, Strobel, H.A.; Heineman, W.R., chemical instruments: Systematization method (Chemical Instrumentation:A SystematicApproach), 3rd dd. (Wiley ﹠amp; Sons:New York 1989)).After this identify impurity, for example, by its relative position in color atlas, wherein the position in the color atlas is expelled in the chromatographic column to the special component wash-out and by the timings in several minutes between the detector by measure sample usually.Relative position in the color atlas is called " retention time ".According to instrument working conditions and a lot of other factors, retention time every day or even among one day, all changing.In order to reduce to influence the accurate identification that these variations are used for impurity, the operator identifies impurity with " relative retention time " (" RRT ").(Strobel p.922)。The RRT of impurity is the retention time of its retention time divided by reference marker.In theory, atomoxetine hcl itself can be used as reference marker, but in fact it accounts for significant proportion so that can make pillar saturated in mixture, and owing to peak-peak can be drifted about, cause to repeat retention time (Strobel, Fig.24.8 (b) p.879, for example understands observed unsymmetrical peak when pillar overloads).Therefore, it is favourable with the sort of compound as reference marker also to selecting the compound except that API, in mixture, add or be present in this compound quantity in the mixture even as big as with detection and little to being not enough to saturated pillar.

The compound that the technician understands at relative pure state in the medication preparation research research and development field can be used as " reference standard ".Reference standard is similar to reference marker, only is used for qualitative analysis, but also be used for unknown mixture reference standard compound quantitatively.When the solution of the concentration known of reference standard and unknown mixture during with constructed analysis, reference standard be " external standard " (Strobel p.924, Snyder p.549, Snyder, L.R.; Kirkland, JJ. modern liquid chromatography introduction (Introduction to Modern Liquid Chromatography), 2nd ed. (John Wiley ﹠amp; Sons:New York 1979)).Can measure the amount of compound in the mixture by the response intensity that compares detector.Also, be attached to herein by reference with reference to U.S. Patent number 6,333,198.

If be scheduled to the poor sensitivity other " response factor " of compensation detector to two kinds of compounds, reference standard also can be used for another kind of compound in the quantitative mixture.(Strobel p.894)。For this purpose, in mixture, directly add reference standard, and be called " interior mark " (Strobel p.925, Snyder p.552).

When not adding reference standard, but when unknown mixture comprises the reference standard compound of detection limit with so-called " standard adding " technology, reference standard even can be used as interior mark.In " standard adding ", prepare two kinds of samples at least by the interior mark that adds known and different quantities.(Strobel pp.391-393，Snyder pp.571，572)。By detector response is mapped to the amount that joins the reference standard in every kind of sample, and the extension chart is to zero point, can measure the detector response ratio that causes without the reference standard that exists in the mixture that adds (referring to for example, Strobel, Figure 11 .4p.392).

As is known to persons skilled in the art, by understanding its chemical structure and route of synthesis, and be tested and appraised the parameter that influences impurity level in the product in the end and come the control of strengthening process impurity greatly.

The accompanying drawing summary

Fig. 1 shows the typical color atlas of the ATM-HCl impurity that obtains by GC on HP-35:35% phenyl methyl siloxanes (HewlettPackard cat.N ° 19091G-113) pillar.

Fig. 2 shows the typical color atlas of the 2-fluorotoluene impurity that obtains by GC on Zebron ZB-WAX 100% polyoxyethylene glycol (Phenomenex cat.N ° 7KK-G007-22) pillar.

Fig. 3 demonstration is passed through the achirality chromatographic instrument at YMC-Pack ODS-AQ, the typical color atlas of the D-ATM that obtains on the S-5 μ m pillar.

Fig. 4 shows the typical color atlas of the atomoxetine hcl that obtains by the chiral chromatography instrument on CHIRALCEL OD-R cellulose iii (3,5-3,5-dimethylphenyl carbamate) pillar.

Summary of the invention

In first embodiment, the object of the invention is isolating atomoxetine hcl impurity; The isolating hydrochloride of N-methyl-3-(3-methylphenoxy)-3-phenylpropylamine (3-ATM HCl).

In another embodiment, the object of the invention is to prepare the method for 3-ATM HCl, by reacting under the definite below processing condition of the alkoxide (alkolate) of 3-fluorotoluene (3FT) and N-methyl-3-hydroxyl-3-phenylpropylamine.

And in another embodiment, the object of the invention is to prepare the method for another kind of atomoxetine hcl impurity N-methyl-3-(4-methylphenoxy)-3-phenylpropylamine (4-ATM HCl), by reacting under the definite below processing condition of the alkoxide of 4-fluorotoluene (4FT) and N-methyl-3-hydroxyl-3-phenylpropylamine.

And in another embodiment, the object of the invention is to prepare the method for another kind of atomoxetine hcl impurity N-methyl-3-phenoxy group-3-phenylpropylamine (D-ATM HCl), by reacting under the definite below processing condition of the alkoxide of fluorobenzene (FB) and N-methyl-3-hydroxyl-3-phenylpropylamine.

In one embodiment, the object of the invention is in the atomoxetine hcl qualitative analysis method as the use of the 3-ATM HCl of reference marker and two kinds of atomoxetine hcl impurity 4-ATM HCl and D-ATM HCl.

In another embodiment, the object of the invention is a kind of with 3-ATM HCl, 4-ATM HCl and the D-ATM HCl method as the quantitative atomoxetine hcl purity of reference standard analysis.

And in another embodiment, the object of the invention is the method for 3FT, 4FT and FB amount of impurities limit in a kind of 2FT raw material of the atomoxetine hcl that is given for synthetic required purity, and this method comprises uses 3-ATM HCl, 4-ATM HCl and D-ATM HCl as reference standard.

In another embodiment, the object of the invention is a kind of atomoxetine hcl purity quantitative methods, comprise using 3-ATM HCl, 4-ATM HCl and D-ATM HCl as reference standard, wherein reference standard or make external standard or do in mark.

In one embodiment, the object of the invention is a kind of analytical procedure of the 2-of being used for fluorotoluene purity check.

In another embodiment, the object of the invention is a kind ofly to comprise restriction and be used for the method for atomoxetine hcl synthetic 2FT raw material impurity 3FT, 4FT and FB quantity, at least aly among 3-ATM HCl, 4-ATM HCl and the D-ATM HCl determines that as reference standard the quantity of 3FT, 4FT and FB in 2-fluorotoluene raw material is to guarantee the atomoxetine hcl product purity by using.

And in another embodiment, the object of the invention is a kind of GC method of novelty of three kinds of impurity that are used for measuring the atomoxetine hcl sample.In further embodiment, the present invention indicates a kind of GC method that is used for measuring the novelty of 2-fluorotoluene sample 3FT, 4FT and FB.

Detailed Description Of The Invention

Unless otherwise indicated herein, three kinds of impurity that relate in application used herein comprise racemic mixture and enantiopure form.Therefore, for example N-methyl-3-(3-methylphenoxy)-3-phenylpropylamine (with its acronym " 3-ATM HCl ") refers to (±)-N-methyl-3-(3-methylphenoxy)-3-phenylpropylamine or (R) (-)-N-methyl-3-(3-methylphenoxy)-3-phenylpropylamine.

Term used herein " aromatic solvent " refers to C _6-0Aromatic hydrocarbons for example but is not limited to benzene, dimethylbenzene or toluene.

Term used herein " predetermined level " is meant the level of impurity 3-ATM HCl, 4-ATM HCl and D-ATM HCl, i.e. 0.15% the level of measuring by GC or HPLC of being equal to or less than.

Term used herein " isolating " refers to be judged by GC or HPLC and to be at least 80% pure compound, preferably at least 90%, even more preferably at least 95%, and most preferably at least 99%.

" reference marker " used in position according to them in the qualitative analysis of identifying mix ingredients, for example, and in chromatogram or thin-layer chromatography (TLC) plate.(Strobel pp.921，922，953)。For this purpose, if existing, compound need not in mixture, add compound in mixture." reference marker " only is used for qualitative analysis, and reference standard can be used for quantitatively or qualitative analysis, or is used for two kinds of analyses.Therefore, reference marker is the part of reference standard, and is included in the definition of reference standard.

Term used herein " reference standard " refers to the compound of the quantitative and qualitative analysis that can be used for active pharmaceutical ingredient.For example, the HPLC of compound or GC retention time can be used for determining relative retention time, therefore may do qualitative analysis.Being expelled in the solution before HPLC or the GC pillar compound concentrations can make comparisons with area under HPLC or the GC peak, therefore can do quantitative analysis.

In above-mentioned general terms, reference standard has been described.Yet it will be appreciated by those skilled in the art that, detector response can be, the peak height of the color atlas that for example obtains or the peak area of integration, for example by UV or specific refractory power detection method, from the elutriant of HPLC system detect or, for example ionic flame detects (FID) or thermal conductivity detection method, detect from the elutriant of gas-chromatography, or other detector response, for example, the UV specific absorption of spot on fluorescence TLC plate.The position of reference standard can be used for calculating the relative retention time that is used for atomoxetine hcl and atomoxetine hcl impurity.

Term used herein " substantially " is meant that RRT is identical substantially, promptly injects overall relative standard deviation for 6 times and is equal to or less than 5%.

The object of the invention is a kind of impurity of the atomoxetine hcl of not identifying in the past, its preparation is with the preparation of other known impurities, and the object of the invention is that these impurity are used for the quantitative use of atomoxetine hcl purity check as reference standard, and is the same with requirement in the manufacturing of high-purity hydrochloric acid Tomoxetine hydrochloride.

Three kinds of hydrochloride impurity in (±) tomoxetine solution and the finished product, have been identified.These three kinds of hydrochloride impurity are a kind of compound N-methyl-3-(3-methylphenoxy)-3-phenylpropylamine (3-ATM HCl) of not identifying in the past, and the hydrochloride of the hydrochloride of N-methyl-3-(4-methylphenoxy)-3-phenylpropylamine (4-ATM HCl) and N-methyl-3-phenoxy group-3-phenylpropylamine (D-ATM HCl).These three kinds of hydrochloride impurity form by the alkoxide reaction with N-methyl-3-hydroxyl-3-phenylpropylamine of 3-fluorotoluene (3FT), 4-fluorotoluene (4FT) and fluorobenzene (FB) respectively.Find to remove shockingly difficulty of these hydrochloride impurity with conventional purification step.

The invention provides a kind of isolating atomoxetine hcl impurity, N-methyl-3-(3-methylphenoxy)-3-phenylpropylamine (3-ATM HCl) has structure:

This 3-ATM HCl impurity is the regional isomer of Tomoxetine hydrochloride.

The invention provides a kind of by the 2-fluorotoluene impurity 3-fluorotoluene and the method for the alkoxide prepared in reaction 3-ATM HCl of N-methyl-3-hydroxyl-3-phenylpropylamine.This method comprises:

A) in temperature at least 90 ℃ and in the presence of highly basic, N-methyl-3-(3-methylphenoxy)-3-phenylpropylamine combines with DMSO;

B) add 3-fluorotoluene and kept reaction mixture at least 5 hours;

C) in reaction mixture, add first kind of organic solvent and water;

D) reclaim (±) 3-methyl tomoxetine alkali crude product;

E) at C _1-4Pure and mild aromatic solvent exists down, and (±) 3-methyl tomoxetine alkali crude product combines with (S)-(+)-amygdalic acid, and to be heated to temperature be about 65 ℃-Yue 70 ℃;

F) reclaim 3-methyl tomoxetine (S)-(+)-mandelate;

G) 3-methyl tomoxetine (S)-(+)-mandelate combines with second kind of organic solvent, water and alkali;

H) reclaim 3-methyl tomoxetine alkali;

I) 3-methyl tomoxetine alkali is changed into corresponding hydrochloride.

In step a), add relatively small amount DMSO, and even think that DMSO is a catalyzer.Preferably, the DMSO amount is about 0.1～about 20mol in every mole of N-methyl-3-hydroxyl-3-phenylpropylamine.Most preferably, the DMSO amount is about 3～about 4 moles in every mole of N-methyl-3-hydroxyl-3-phenylpropylamine.

Highly basic can be NaOH, KOH, Ca (OH) in step a) ₂Or Ba (OH) ₂In any.Preferably, highly basic is KOH.Having alkali number in preferred every mole of N-methyl-3-hydroxyl-3-phenylpropylamine is about 3～about 4 moles.

Preferably the amount of the 3-fluorotoluene that adds in every mole of N-methyl-3-hydroxyl-3-phenylpropylamine in step b) is at least 2 moles.

Preferably first kind of organic solvent is selected from C in step c) _5-10Aliphatics and aromatic hydrocarbons, aromatic hydrocarbons can be by one or more (preferred 1～3 kinds) C _1-3Alkyl, C _3-8Alkyl ester and C _3-8Alkyl oxide replaces.More preferably, organic solvent is selected from toluene, benzene, dimethylbenzene, diisopropyl ether, methyl-tert-butyl ether (methyl-tert-butyl), ethyl acetate, n-butyl acetate (ethyl acetaten-butylacetate) and isobutyl acetate.Most preferably, organic solvent is a toluene.

Preferably in step e), add C in every 1g (±) 3-methyl tomoxetine alkali _1-4The amount of alcohol is about 0.1ml.Most preferably, C _1-4Alcohol is methyl alcohol.Aromatic solvent can be by one or more (preferred 1～3 kinds) C _1-10Alkyl, for example aromatic hydrocarbon of toluene, benzene, dimethylbenzene replacement.The first-selected toluene of organic solvent.Preferably, after the heating, it is about 0 ℃-Yue 20 ℃ that reaction mixture is cooled to temperature.Preferably, to be cooled to temperature be about 5 ℃-Yue 10 ℃ to reaction mixture.

Preferred steps g) alkali is selected from alkaline earth metal hydroxides in, for example NaOH or KOH, or alkaline earth metal carbonate Na for example ₂CO ₃Or K ₂CO ₃Most preferably, alkali is NaOH.

Preferred steps g) second kind of organic solvent is selected from for example C of aliphatics or aromatic hydrocarbons in _5-8Alkane, toluene and dimethylbenzene, C _1-4Alkyl ester is methyl acetate, ethyl acetate, n-butyl acetate and isobutyl acetate for example, and ketone is methylethylketone for example, C straight chain or side chain _4-8Alcohol is propyl carbinol, 2-butanols and Pentyl alcohol or their mixture for example.More preferably, second kind of organic solvent is selected from methyl acetate, n-butyl acetate and isobutyl acetate.Most preferably, second kind of organic solvent is n-butyl acetate.

U.S. Patent number 4,018,895 to disclose second kind of impurity be N-methyl-3-(4-methylphenoxy)-3-phenylpropylamine (4-ATM HCl), and have structure:

This 4-ATM compound is the regional isomer of Tomoxetine hydrochloride.

The invention provides a kind of by the 2-fluorotoluene a kind of impurity 4-fluorotoluene and the processing condition that are used for 3-ATM HCl preparation described in the above of the alkoxide of N-methyl-3-hydroxyl-3-phenylpropylamine under its method of prepared in reaction.

The third impurity be N-methyl-3-hydroxyl-3-phenylpropylamine or " D-ATM HCl " (D-ATM).U.S. the patent No. 4,018, and 895 disclose this compound, and have structure:

The invention provides a kind of by the 2-fluorotoluene a kind of impurity fluorobenzene and the processing condition that are used for 3-ATM HCl preparation described in the above of the alkoxide of N-methyl-3-hydroxyl-3-phenylpropylamine under the method for prepared in reaction D-ATM impurity.

By independent synthetic these three kinds of impurity of identifying, wherein by comprising the 3FT that known quantity is about 2% (weight ratio separately) (3-fluorotoluene), 4FT (4-fluorotoluene) and FB (fluorobenzene), 2FT (2-fluorotoluene) have a mind to prepare (±) TMX.The relative quantity of the corresponding by product that forms in the reaction detects by the GC area percentage, meets the aromatic series activation to nucleophilic displacement of expection.The amount of D-ATM HCl that promptly derives from FB is much larger than the amount of the 3-ATM HCl that derives from 3FT, and the amount of 3-ATM HCl that derives from 3FT is again much larger than the amount of the 4-ATM HCl that derives from 4FT.The relative quantity of finding these impurity also meets expection above reacting the 2FT that reclaims the back.Be the amount that the amount of FB is less than 3FT, the amount of 3FT is less than the amount of 4FT.Table 1 provides these results

Table 1

Sample	FB	2FT	3FT	4FT
					Initial 2FT forms	1.46％	94.30％	2.12％	1.98％
Distillment (comprising excessive 2FT and impurity)	0.56％	95.45％	1.18％	2.19％
						D-ATM	ATM	3-ATM	4-ATM
Reaction finishes TMX alkali	5.97％	88.07％	4.41％	1.35％
					Finish the purification of factor of TMX alkali to reaction from 2FT	0.24	1.07	0.48	1.47

By gas chromatographic analysis derive from hydrochloric acid ATM synthetic progressively (±) tomoxetine and these intermediate products of technology analyze through the GC achirality from ATM, to separate this three kinds of impurity, always produce the peak that comprises two kinds of enantiomorphs.

In purge process, suppose that analytical technology produces the respective peaks of impurity in the sample, then the purification of factor of impurity X can be defined as follows:

(the peak area % of X in the material sample)/(the peak area % of X in the product sample)

This calculating meaning purification of factor is high more, the easy more impurity of removing, even and purification of factor less than 1 show may, remove also unusual difficulty of impurity.

The purification of factor that obtains 3-ATM, 4-ATM and D-ATM impurity is very low usually, and maximum value is 4.56.The value of other impurity is greater than 50, and those impurity can effectively be removed.Find also that in the mandelate stage purification of factor of D-ATM impurity is less than 1.Following tabulation provides detailed analysis, has reported that wherein the purifying of GC area percentage data and calculating is stranded son, and the raw material A % of each impurity that promptly is used for synthetic each step is to the ratio of product A %.

Table 2

Step 2: Tomoxetine hydrochloride (S)-(+) mandelate crude product (ATM-SAM crude product) constitutes

Impurity	(±) TMX solution (A%)	ATM-SAM crude product (A%)	Purification of factor
				D-ATM-SAM	5.97	7.33	0.81
ATM-SAM	88.07	88.30	1.00

3-ATM-SAM	4.41	3.13	1.41
				4-ATM-SAM	1.35	1.21	1.12

Table 3

Step 3: the Tomoxetine hydrochloride of purifying (S)-(+) mandelate (ATM-SAM of purifying) constitutes

Impurity	ATM-SAM crude product (A%)	The ATM-SAM of purifying (A%)	Purification of factor
				D-ATM-SAM	7.33	8.34	0.88
ATM-SAM	88.30	88.32	1.00
				3-ATM-SAM	3.13	2.28	1.37
4-ATM-SAM	1.21	1.05	1.15

Table 4

Step 4 and 5: atomoxetine hcl (ATM HCl) constitutes

Impurity	The ATM-SAM of purifying (A%)	ATM HCl (A％)	Purification of factor
				D-ATM	8.34	3.70	2.25
ATM	88.32	95.60	0.92
				3-ATM	2.28	0.50	4.56
4-ATM	1.05	0.30	3.50

Can use the purification of factor of the amount that is used for calculating D-ATM HCl, 3-ATM HCl and 4-ATM HCl to return the amount of calculating 2-fluorotoluene FB, 3FT and 4FT.Be calculated as follows:

Finally: GC A%	D-ATM HCI 0.15	3-ATM HCI 0.15	4-ATM HCI 0.15
				The intermediate product of purifying: GC A%	pD-ATM-SMA 0.34	p3-ATM-SMA 0.68	p4-ATM-SMA 0.53
Intermediate product crude product: GC A%	cD-ATM-SMA 0.30	C3-ATM-SMA 0.94	C4-ATM-SMA 0.61
				(±)TMX： GC A％	(±)D-TMX 0.24	(±)3-TMX 1.32	(±)4-TMX 0.68
Corresponding 2FT raw material: GC A%	FB 0.059	3FT 0.636	4FT 0.990

Although method comprises five purification steps, i.e. twice extraction and three crystallizations, low surprising of the clearance rate of 3-ATMHCl, 4-ATM HCl and D-ATM HCl.Therefore, as what estimate usually, can not get the atomoxetine hcl of required purity by the purification step that repeats to use this area.Amount by impurity 3FT, 4FT and FB in the restriction raw material 2-fluorotoluene may obtain required purity.Can calculate by above-described purification of factor and determine limiting the quantity of of 3FT, 4FT and FB impurity, condition is to have suitable reference standard to use.

The invention provides and comprise and use 3-ATM HCl, 4-ATM HCl and D-ATM HCl the whole bag of tricks as reference marker or reference standard.

When using the impurity of these enantiomer-pures, they will be with racemic object form in identical retention time by wash-out.

A kind of method of identifying impurity in the atomoxetine hcl sample is provided, comprises:

(a) provide comprise reference marker and atomoxetine hcl with reference to sample;

(b) measure with reference to sample to determine the relative retention time of reference marker with HPLC or GC with respect to atomoxetine hcl;

(c) measure the sample of atomoxetine hcl to determine the relative retention time of impurity with HPLC or GC with respect to atomoxetine hcl;

(d) compare in step (b) and the relative retention time that records (c);

If the relative retention time of determining is identical substantially, identify that impurity is identical with reference marker in step (b) and (c);

Wherein reference marker is selected from 3-ATM HCl, 4-ATM HCl and D-ATM HCl.

The method of the amount of impurity in a kind of definite atomoxetine hcl sample also is provided, comprises:

(a) reference standard of adding known quantity in the atomoxetine hcl sample;

(b) measure atomoxetine hcl with HPLC or GC;

(c) HPLC that evaluation and measurement are relevant with impurity or GC peak area;

(d) HPLC that evaluation and measurement are relevant with reference standard or GC peak area;

(e) according to step (c) and the result (d) calculate the amount of impurity in the atomoxetine hcl sample;

Reference standard is selected from 3-ATM HCl, 4-ATM HCl and D-ATM HCl.

The method of the amount of impurity in a kind of definite atomoxetine hcl sample also is provided, comprises:

(a) provide a kind of atomoxetine hcl sample that comprises unknown concentration impurity;

(b) provide a kind of sample of concentration known impurity;

(c) measure the part of atomoxetine hcl sample and the some of impurity sample with HPLC or GC;

(d) measure the impurity peak area that obtains from atomoxetine hcl sample and impurity sample; And

(e) calculate the concentration of impurity in the atomoxetine hcl sample according to the observed value of step (d);

Impurity is selected from 3-ATM HCl, 4-ATM HCl and D-ATM HCl.

Also provide a kind of atomoxetine hcl that guarantees to prepare the method for purity, comprising:

(a) the predetermined level of selection impurity 3-ATM HCl, 4-ATM HCl and D-ATM HCl;

(b) purification of factor of each impurity that forms in each step of method of measurement synthetic hydrochloric acid Tomoxetine hydrochloride;

(c) calculate the 3-fluorotoluene, 4-fluorotoluene and the fluorobenzene that exist in the 2-fluorotoluene highest level so that in atomoxetine hcl is produced the level of 3-ATM HCl, 4-ATM HCl and D-ATM HCl be lower than predetermined level;

Step (c) comprises 3-ATM HCl, 4-ATM HCl and the D-ATM HCl use as reference standard.

The suitable method of synthetic hydrochloric acid Tomoxetine hydrochloride known in the art comprises 2-fluorotoluene and N-methyl-3-hydroxyl-3-phenylpropylamine reaction and comprises European Patent Publication No EP 0 052492, U.S. Patent number 4,868,344 and 6,541,668 and International Patent Application Publication No. WO00/58262 those disclosed.Usually, the route of synthesis of production Tomoxetine hydrochloride comprises:

I. tomoxetine is synthetic, uses the 2-fluorotoluene as reaction reagent;

II. use the tomoxetine optical resolution of (S)-(+) amygdalic acid as resolving agent; And

III. the generation of atomoxetine hcl with separate.

Analytical procedure

Determine atomoxetine hcl impurity with following gas-chromatography instrument and step:

Pillar and weighting material: HP-35:35% phenmethyl siloxanes

(cat.N ° of 19091G-113 of Hewlett Packard) or Equivalent

Length: 30m

Diameter: 0.32m

Film thickness: 0.25 μ m

Injector temperature: 250 ℃

Detector temperature: 250 ℃

Oven temperature: time (min) temperature 0

180℃

20.0 180℃

23.5 250℃

33.5 250℃

Starting time: 5min

Volume injected: 1 μ l

Carrier gas: nitrogen

Flow velocity: 1.5ml/min

Detector: FID

Splitting ratio: 10/1

The typical retention time that obtains is as follows:

RT RRT

(±)D-ATM 12.8′ 0.81

ATM 15.9′ 1.00

(±)3-ATM 16.9′ 1.06

(±)4-ATM 18.3′ 1.15

Fig. 1 has shown the color atlas of sample.

Be prepared as follows sample solution: about 15mgATM HCl is dissolved in the 1ml water.Then, the ammoniacal liquor that adds 10ml normal hexane and 2ml 5% (volume ratio).Violent biased sample after being separated, is transferred to about 1ml upper organic phase in the injection phial.

Determine 2-fluorotoluene impurity with following gas-chromatography instrument and step:

Pillar and weighting material: Zebron ZB-WAX 100% polyoxyethylene glycol

(Phenomenex cat.N ° 7KK-G007-22) or Equivalent

Length: 60m

Diameter: 0.53m

Film thickness: 1.0 μ m

Injector temperature: 180 ℃

Detector temperature: 200 ℃

Oven temperature: Rate ℃/min temperature keeps Min

60℃ 24

10.0 200℃ 10

Starting time: 3min

Volume injected: 1 μ l

Carrier gas: nitrogen

Flow velocity: 3.0ml/min

Detector: FID

Splitting ratio: 10/1

The typical retention time that obtains is as follows:

RT RRT

Fluorobenzene 14.4 ' 0.65

2-butanols 16.1 ' 0.73

2-fluorotoluene 22.1 ' 1.00

3-fluorotoluene 22.9 ' 1.04

4-fluorotoluene 23.5 ' 1.06

Fig. 2 has shown the color atlas of sample.

Finish the quantitative analysis of Tomoxetine hydrochloride with following achirality HPLC method:

Pillar and weighting material: YMC-Pack ODS-AQ, S-5 μ m, 12nm

250mm×4.6mm×5.0μm，cat n.042574458(W)

Or Equivalent

Damping fluid: NaH2PO4 mono-hydrate pH 3.0: 2.8g goes at 1000mL

In the ionized water, transfer pH 3.0 with H3PO485% (w/w).

Filter with 0.45 μ m strainer.

Elutriant A: acetonitrile: water 90: 10

Gradient time (min) % damping fluid % elutriant A

0 85 15

20 48 52

30 48 52

Starting time: 8 minutes

Flow velocity: 1.5mL/rnins.

Detector: UV is at 215nm

Column temperature: 40 ℃

Diluent damping fluid: acetonitrile (60: 40)

Injection liquid 5 μ L

Standard solution preparation:

Accurately take by weighing about 20mg D-ATM HCl (D-ATM) standard and put in the 100ml volumetric flask and use the diluted constant volume.The solution that 0.5ml is obtained is transferred in the 100ml volumetric flask and is used the diluted constant volume.

The sample solution preparation:

The ATM*HCl sample solution of the about 1.0mg/ml of preparation in diluent.

Step:

Inject blank diluent so that pillar is stable and the recognition system peak, 3 blank are done in suggestion.

The solution of injection standard product and sample makes the color atlas of sample continue up to the gradient EP (end of program) in chromatographic instrument.

The color atlas of sample is shown in Fig. 3.

Determine the purity of enantiomorph by following chirality HPLC method:

Pillar and weighting material: CHIRALCEL OD-R cellulose iii (3, the 5-3,5-dimethylphenyl

Carbamate) 250mm * 4.60mm * 10um

(Daicel chemicals cat.NA DAIC 14625) or etc.

The valency thing

Moving phase: KPF6100mM/ACN-60/40

Attention: color atlas lasted till 30 minutes always

Sample volume: 5.0 μ L

Flow velocity: 0.8mL/min.

Detector: UV is at 215nm

Column temperature: 35 ℃

The diluent flow phase

For can changing moving phase, the system flexibility that obtains to need forms and flow velocity.

The color atlas of sample is shown in Fig. 4.

Embodiment:

Though described the present invention with certain embodiments and embodiment preferred, be appreciated that the present invention is not limited to these embodiment and embodiment.Therefore, the present invention includes the change of specific embodiment described herein and preferred embodiment, this will be apparent to those skilled in the art.

Embodiment 1

Synthesizing of N-methyl-3-(3-methylphenoxy)-3-phenylpropylamine (3-ATM HCl)

6g (0.969mol) dimethyl sulfoxide (DMSO), 40g (0.242mol) N-methyl-3-hydroxyl-3-phenylpropylamine (100%, mw165.12) and 75.5g (1.211mol) potassium hydroxide (technical grade, 90% measures) in batches 100 ℃ ± 3 ℃ heated and stirred 1 hour.The mixture to 80 ℃ of cooling gained, and fully stir, in about 1 hour, add 79.95g (0.726mol) 3-fluorotoluene, maintain the temperature at 83 ℃ ± 3 ℃, cause the salt precipitation.Stirred the mixture about 5 hours at 83 ℃ ± 3 ℃ then, add 300ml water and 300ml toluene.Stirred the mixture several minutes, and make and be separated.With 50ml toluene aqueous phase extracted, collect organic phase and use 80ml water washing three times.To produce about 70g brown liquid residue, it is (±) 3-methyl tomoxetine alkali (3-TMX) crude product that comprises about 0.2mol 100% alkali in the organic phase of about 60 ℃-Yue 80 ℃ of vacuum concentration washing.Add (S)-(+) amygdalic acid of 400ml toluene, 3ml methyl alcohol and 19.0g (0.125mol) at 25 ℃, the soup compound of generation is heated to temperature and is about 65 ℃-Yue 70 ℃ and forms solution to dissolving fully.The solution that cools off gained then causes solid 3-methyl tomoxetine (S)-(+) mandelate (3-ATM-SMA) crystallization to about 5 ℃-Yue 10 ℃, by filtering separation, and discovery difficulty and slow, and use toluene wash, find also difficulty and slow.

After drying under about 50 ℃-Yue 60 ℃ of vacuum, reclaim the 30g product.

30g exsiccant 3-ATM-SMA mixes with 150ml n-butyl acetate and 150ml water under stirring at room.The aqueous sodium hydroxide solution that adds about 11g30% is regulated pH and is arrived approximately 12.5, makes to be separated.Comprise the organic phase twice of 3-ATM alkali with the 30ml water washing, use filter paper filtering, and use as follows in the preparation of hydrochloride afterwards.

When stirring, maintain the temperature between about 15 ℃ and about 25 ℃, in filterable organic phase, drip the hydrochloride aqueous solution of 8.55g36%, cause (mw291.82) crystallization of 3-ATM hydrochloride and suspendible with ice-water bath.Stirred suspension 1 hour at about 20 ℃, by solid collected by filtration, with 35ml n-butyl acetate washed twice, drying is 18 hours under about 50 ℃-Yue 60 ℃ of vacuum, produces about 19.6g product, and fusing point is about 159 ℃-Yue 160 ℃, and ¹The H-NMR data are 9.58ppm, bs, 2H; 7.35-7.20ppm, m, 5H; 7.01ppm, t, 1H; 6.68-6.65ppm, m, 2H; 6.59ppm, dd, 1H; 5.30ppm, dd, 1H; 3.10ppm, quint, 2H; 2.57ppm, t, 3H; 2.41ppm, m, 2H; 2.22ppm, s, 3H.According to initial N-methyl-3-hydroxyl-3-phenylpropylamine yield is 28% weight ratio.Determine that 3-ATMHCl is the mixture of enantiomorph, record by chirality HPLC that to compare be 99/1.

Embodiment 2

Synthesizing of N-methyl-3-(4-methylphenoxy)-3-phenylpropylamine (4-ATM)

76g (0.969mol) dimethyl sulfoxide (DMSO), 40g (0.242mol) N-methyl-3-hydroxyl-3-phenylpropylamine (100%, mw165.12) and 75.5g (1.211mol) potassium hydroxide (technical grade, 90% measures) in batches 100 ℃ ± 3 ℃ heated and stirred 1 hour.The mixture to 80 ℃ of cooling gained then, under fully stirring, added 79.95g (0.726mol) 3-fluorotoluene in about 1 hour, maintain the temperature at 83 ℃ ± 3 ℃, caused the salt precipitation.Stirred the mixture about 5 hours at 83 ℃ ± 3 ℃ then, and add 300ml water and 300ml toluene.Stirred the mixture several minutes, and made to be separated.With 50ml toluene aqueous phase extracted, collect organic phase and use 80ml water washing three times.The organic phase of thickening and washing is to produce about 70g (±) 4-methyl tomoxetine alkali (4-TMX) crude product brown liquid residue (about 0.2mol 100% alkali) under about 60 ℃-Yue 80 ℃ of vacuum.Add (S)-(+) amygdalic acid of 400ml toluene, 3ml methyl alcohol and 19.0g (0.125mol) at 25 ℃, it is about 65 ℃-Yue 70 ℃ that the soup compound of generation is heated to temperature.Cool off the solution to 0 ℃ 2 hours of gained then.Filtering separation solid 4-methyl tomoxetine (S)-(+) mandelate (4-ATM-SMA) is used toluene wash, and is optional with the 40mlMTBE washing, and dry under about 50 ℃-Yue 60 ℃ of vacuum, produces the 50g product.

50g exsiccant 4-ATM-SMA mixes with 250ml acetate (just) butyl ester and 250ml water under stirring at room.The aqueous sodium hydroxide solution that adds about 21g30% is regulated pH and is arrived approximately 12.5, makes to be separated.Comprise the organic phase twice of 4-ATM alkali with the 30ml water washing, use filter paper filtering, and use as follows in the preparation of hydrochloride afterwards.

When stirring, maintain the temperature between about 15 ℃ and about 25 ℃, add the hydrochloride aqueous solution of 14.25g36% to filterable organic phase with ice-water bath.The large quantities of crystallizations of hydrochloric acid 4-ATM (mw29.82) add the 40ml n-butyl acetate stirring are carried out.The suspension of gained stirred 1 hour at about 20 ℃, pass through solid collected by filtration, with about 40ml n-butyl acetate washed twice, and under about 50 ℃-Yue 60 ℃ of vacuum dry 18 hours, produce about 23.5g product, fusing point is about 164 ℃-Yue 167 ℃, and 33% yield calculates according to N-methyl-3-hydroxyl-3-phenylpropylamine raw material.Find that by chirality HPLC 4-ATM HCl is the mixture of enantiomorph, comparing is 58: 42.

Embodiment 3

Synthesizing of N-methyl-3-phenoxy group-3-phenylpropylamine (D-ATM)

G (0.969mol) dimethyl sulfoxide (DMSO), 40g (0.242mol) N-methyl-3-hydroxyl-3-phenylpropylamine (100%, mw165.12) and 75.5g (1.211mol) potassium hydroxide (technical grade, 90% measures) in batches 100 ℃ ± 3 ℃ heated and stirred 1 hour.The mixture to 80 ℃ of cooling gained then, under fully stirring, added 69.77g (0.726mol) fluorobenzene in about 1 hour, maintain the temperature at 83 ℃ ± 3 ℃, made the salt crystallization.Stirred the mixture about 5 hours at 83 ℃ ± 3 ℃ then, add 300ml water and 300ml toluene, and stirred the mixture several minutes.Make then to be separated, and with 50ml toluene aqueous phase extracted.Collect organic phase, and with 80ml water washing three times.The organic phase of thickening and washing produces about 70g brown liquid residue under about 60 ℃-Yue 80 ℃ of vacuum, and for example, the holder of (±) demethyl is not

West spit of fland alkali (D-TMX) crude product (100% alkali of about 0.2mol).

Add (S)-(+) amygdalic acid of 400ml toluene, 3ml methyl alcohol and 19.0g (0.125mol) at 25 ℃, it is about 65 ℃-Yue 70 ℃ (not dissolvings fully) that the soup compound of generation is heated to temperature, is cooled to about 5 ℃-Yue 10 ℃ then.By filtering separation solid D-ATM HCl (S)-(+)-mandelate (D-ATM-SMA), use toluene wash, and dry under about 50 ℃-Yue 60 ℃ of vacuum, produce the 48g product.48g exsiccant D-ATM-SMA mixes with 250ml n-butyl acetate and 250ml water under stirring at room.The aqueous sodium hydroxide solution that adds about 16g30% is regulated pH and is arrived approximately 12.5, and makes and is separated.Comprise the organic phase twice of D-ATM alkali with the 35ml water washing, use filter paper filtering, and use as follows in the preparation of hydrochloride afterwards.

When stirring, maintain the temperature between about 15 ℃ and about 25 ℃, in filterable organic phase, drip the hydrochloride aqueous solution of 12.3g 36%, cause hydrochloric acid D-ATM (mw277.80) crystallization with ice-water bath.The suspension of gained stirred 1 hour at about 20 ℃, pass through solid collected by filtration, with 40ml n-butyl acetate washed twice, and under about 50 ℃-about 60 ℃ of vacuum dry 18 hours, produce the 32.7g product, the yield that calculates according to N-methyl-3-hydroxyl-3-phenylpropylamine raw material is 48%, and fusing point is about 170 ℃-Yue 174 ℃.Find that by chirality HPLC D-ATM HCl is the mixture of enantiomorph, comparing is 69: 31.

Claims (14)

1. an isolating hydrochloric acid N-methyl-3-(3-methylphenoxy)-3-phenylpropylamine.

2. method for preparing hydrochloric acid N-methyl-3-(3-methylphenoxy)-3-phenylpropylamine (3-ATMHCl) comprises:

(a) in temperature at least 90 ℃ and in the presence of highly basic, N-methyl-3-hydroxyl-3-phenylpropylamine combines with DMSO;

(b) add 3-fluorotoluene and kept reaction mixture at least 5 hours;

(c) in reaction mixture, add first kind of organic solvent and water;

(d) reclaim (±) 3-methyl tomoxetine alkali crude product;

(e) at C _1-4Pure and mild aromatic solvent exists down, and (±) 3-methyl tomoxetine alkali crude product combines with (S)-(+)-amygdalic acid, and to be heated to temperature be about 65 ℃-Yue 70 ℃;

(f) reclaim 3-methyl Tomoxetine hydrochloride (S)-(+)-mandelate;

(g) 3-methyl Tomoxetine hydrochloride (S)-(+)-mandelate combines with second kind of organic solvent, water and alkali;

(h) reclaim 3-methyl Tomoxetine hydrochloride alkali; And

(i) 3-methyl Tomoxetine hydrochloride alkali is transformed into its hydrochloride.

3. the method for claim 2, wherein step (a) comprises that every mole of N-methyl-3-hydroxyl-3-phenylpropylamine is in conjunction with about 0.1-20 mole DMSO, highly basic is KOH, the amount of the 3-fluorotoluene that adds in every mole of N-methyl-3-hydroxyl-3-phenylpropylamine in step (b) is at least 2 moles, first kind of organic solvent in the step (c) is selected from toluene, benzene, dimethylbenzene, diisopropyl ether, methyl-tert-butyl ether, ethyl acetate, n-butyl acetate and isobutyl acetate, and C in the step (e) _1-4Alcohol is that methyl alcohol and add-on are the about 0.1ml of every 1g (±) 3-methyl Tomoxetine hydrochloride alkali.

4. method for preparing hydrochloric acid N-methyl-3-(4-methylphenoxy)-3-phenylpropylamine (4-ATMHCl) comprises:

(a) in temperature at least 90 ℃ and in the presence of highly basic, N-methyl-3-hydroxyl-3-phenylpropylamine combines with DMSO;

(b) add 4-fluorotoluene and kept reaction mixture at least 5 hours;

(c) in reaction mixture, add first kind of organic solvent and water;

(d) reclaim (±) 4-methyl tomoxetine alkali crude product;

(e) at C _1-4Pure and mild aromatic solvent exists down, and (±) 4-methyl tomoxetine alkali crude product combines with (S)-(+)-amygdalic acid, and to be heated to temperature be about 65 ℃-Yue 70 ℃;

(f) reclaim 4-methyl Tomoxetine hydrochloride (S)-(+)-mandelate;

(g) 4-methyl Tomoxetine hydrochloride (S)-(+)-mandelate combines with second kind of organic solvent, water and alkali;

(h) reclaim 4-methyl Tomoxetine hydrochloride alkali; And

(i) 4-methyl Tomoxetine hydrochloride alkali is transformed into its hydrochloride.

5. the method for claim 4, wherein step (a) comprises that every mole of N-methyl-3-hydroxyl-3-phenylpropylamine is in conjunction with about 0.1-20 mole DMSO, highly basic is KOH, the amount of the 4-fluorotoluene that adds in every mole of N-methyl-3-hydroxyl-3-phenylpropylamine in step (b) is at least 2 moles, first kind of organic solvent in the step (c) is selected from toluene, benzene, dimethylbenzene, diisopropyl ether, methyl-tert-butyl ether, ethyl acetate, n-butyl acetate and isobutyl acetate, and C in the step (e) _1-4Alcohol is that methyl alcohol and add-on are the about 0.1ml of every 1g (±) 4-methyl Tomoxetine hydrochloride alkali.

6. method for preparing hydrochloric acid N-methyl-3-phenoxy group-3-phenylpropylamine (D-ATM HCl) comprises:

(a) in temperature at least 90 ℃ and in the presence of highly basic, N-methyl-3-hydroxyl-3-phenylpropylamine combines with DMSO;

(b) add fluorobenzene and kept reaction mixture at least 5 hours;

(c) in reaction mixture, add first kind of organic solvent and water:

(d) reclaim (±) D-tomoxetine alkali crude product;

(e) at C _1-4Pure and mild aromatic solvent exists down, and (±) D-tomoxetine alkali crude product combines with (S)-(+)-amygdalic acid, and to be heated to temperature be about 65 ℃-Yue 70 ℃;

(f) reclaim D-Tomoxetine hydrochloride (S)-(+)-mandelate;

(g) D-Tomoxetine hydrochloride (S)-(+)-mandelate combines with second kind of organic solvent, water and alkali;

(h) reclaim D-Tomoxetine hydrochloride alkali; And

(i) 4-methyl Tomoxetine hydrochloride alkali is transformed into its hydrochloride.

7. the method for claim 6, wherein step (a) comprises that every mole of N-methyl-3-hydroxyl-3-phenylpropylamine is in conjunction with about 0.1-20 mole DMSO, highly basic is KOH, the amount of the fluorobenzene that adds in every mole of N-methyl-3-hydroxyl-3-phenylpropylamine in step (b) is at least 2 moles, first kind of organic solvent in the step (c) is selected from toluene, benzene, dimethylbenzene, diisopropyl ether, methyl-tert-butyl ether, ethyl acetate, n-butyl acetate and isobutyl acetate, and C in the step (e) _1-4Alcohol is that methyl alcohol and add-on are the about 0.1ml of every 1g (±) D-methyl Tomoxetine hydrochloride alkali.

8. method of identifying atomoxetine hcl sample impurity comprises:

(a) provide comprise reference marker and atomoxetine hcl with reference to sample;

(b) measure with reference to sample to determine the relative retention time of reference marker with HPLC or GC with respect to atomoxetine hcl;

(c) measure the sample of atomoxetine hcl to determine the relative retention time of impurity with HPLC or GC with respect to atomoxetine hcl;

(d) compare in step (b) and the relative retention time of determining (c);

If the relative retention time of determining is identical substantially, identify that then impurity is identical with reference marker in step (b) and (c);

Wherein reference marker is selected from 3-ATM HCl, 4-ATM HCl and D-ATM HCl.

9. the method for claim 8, wherein reference marker is hydrochloric acid N-methyl-3-(3-methylphenoxy)-3-phenylpropylamine.

10. the metering method of impurity in the definite atomoxetine hcl sample comprises:

(a) reference standard of adding known quantity in the atomoxetine hcl sample;

(b) measure the atomoxetine hcl sample with HPLC or GC;

(c) HPLC that evaluation and measurement are relevant with impurity or GC peak area;

(d) HPLC that evaluation and measurement are relevant with reference standard or GC peak area;

(e) according to step (c) and the result (d) calculate the amount of impurity in the atomoxetine hcl sample;

Wherein reference standard is selected from 3-ATM HCl, 4-ATM HCl and D-ATM HCl.

11. the method for claim 10, wherein reference standard is hydrochloric acid N-methyl-3-(3-methylphenoxy)-3-phenylpropylamine.

12. the metering method of impurity in the definite atomoxetine hcl sample comprises:

(a) provide the atomoxetine hcl sample that comprises unknown concentration impurity;

(b) provide the sample of concentration known impurity;

(c) measure the part of atomoxetine hcl sample and the some of impurity sample with HPLC or GC;

(d) measure the impurity peak area that obtains from atomoxetine hcl sample and impurity sample; And

(e) calculate the concentration of impurity in the atomoxetine hcl sample according to the observed value of step (d);

Wherein impurity is selected from 3-ATM HCl, 4-ATM HCl and D-ATM HCl.

13. the method for claim 12, wherein the impurity in the step (b) is hydrochloric acid N-methyl-3-(3-methylphenoxy)-3-phenylpropylamine.

14. a method that guarantees the purity of atomoxetine hcl preparation comprises:

(a) the predetermined level of selection impurity 3-ATM HCl, 4-ATM HCl and D-ATM HCl;

(b) purification of factor of each impurity that forms in each step of method of measurement synthetic hydrochloric acid Tomoxetine hydrochloride;

(c) calculate the highest level that can be present in 3-fluorotoluene, 4-fluorotoluene and fluorobenzene in the 2-fluorotoluene so that 3-ATM HCl, 4-ATMHCl in the atomoxetine hcl that produces and the level of D-ATM HCl are lower than predetermined level;

Wherein step (c) comprises that use 3-ATM HCl, 4-ATM HCl and D-ATM HCl are as reference standard.

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