CN108929236A - The preparation of tomoxetine hydrochloride - Google Patents
The preparation of tomoxetine hydrochloride Download PDFInfo
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- CN108929236A CN108929236A CN201710382278.3A CN201710382278A CN108929236A CN 108929236 A CN108929236 A CN 108929236A CN 201710382278 A CN201710382278 A CN 201710382278A CN 108929236 A CN108929236 A CN 108929236A
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- compound
- methyl
- phenoxy group
- acetone
- amphetamine
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- MHHJRJYLUMMRDG-XNWIYYODSA-N [FH+]CC[C@H](CC1CC2=CC2)C1I Chemical compound [FH+]CC[C@H](CC1CC2=CC2)C1I MHHJRJYLUMMRDG-XNWIYYODSA-N 0.000 description 1
Classifications
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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
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
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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
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention belongs to pharmaceutical technology fields, and in particular to a method of prepare the tomoxetine hydrochloride that N- methyl -3- phenoxy group-amphetamine content is less than 0.2%.Tomoxetine hydrochloride is first, and for treating the non-upper of children's hyperkinetic syndrome, it is a kind of highly selective norepinephrine reuptake inhibitors, extremely low with other neurotransmitter affinity, will not induce and twitch symptom or increase dyskinesia.N- methyl -3- phenoxy group-amphetamine is tomoxetine hydrochloride process impurity, it is difficult purification removal because structure is similar, provide that N- methyl -3- phenoxy group-amphetamine content is not higher than 0.3 according to European Pharmacopoeia, the present invention can be effectively controlled N- methyl -3- phenoxy group-amphetamine content in product, improve drug quality.
Description
Technical field
The invention belongs to medical sciences, field of medicinal chemistry.
Background technique
Tomoxetine hydrochloride, chemical name：(R)-N- methyl -3- (2- methylphenoxy) -3- phenylpropyl amine hydrochlorate, is only
One acquisition U.S. FDA ratifies the non-central nervous excitation agent for treating attention-deficit hyperactivity disease obstacle.Tomoxetine hydrochloride is
A kind of highly selective norepinephrine reuptake inhibitors, it is extremely low with other neurotransmitter affinity, twitch will not be induced
Symptom increases dyskinesia.Impurity N- methyl -3- phenoxy group-amphetamine is tomoxetine hydrochloride process impurity, because of structure phase
Seemingly it is difficult purification removal, provides that its content must not be higher than 0.3% according to European Pharmacopoeia.
Summary of the invention
0.2% is less than the invention discloses a kind of control impurity N- methyl -3- phenoxy group-amphetamine content and yield is opposite
Higher tomoxetine hydrochloride preparation method, this method can be effectively controlled impurity content in product and stable content will not be with storage
It deposits the extension of time and increases, improve drug quality.Structure is as follows：
。
The present invention mainly passes through the reasonable Quality Control of synthesis technology of tomoxetine hydrochloride, to reach N- methyl -3- in kind of product
Phenoxy group-amphetamine content is less than 0.2%.It is with compound I and compound II substitution reaction that tomoxetine hydrochloride, which obtains preparation process,
Obtain intermediate compound III, compound III obtains R configuration intermediate compound IV by splitting for several times, in organic solvent with chlorination
Hydrogen obtains finished product tomoxetine hydrochloride at salt.Specific route is as follows：
。
Step 1 is the substitution reaction of compound I Yu compound II, is the work that N- methyl -3- phenoxy group-amphetamine generates
Skill step.
Reaction dissolvent used in step 1 can be one or more selected from the following：N,N-Dimethylformamide, two
Six ring of oxygen, dimethyl sulfoxide, 1,3- dimethyl-imidazolinone, N-Methyl pyrrolidone.
Step 1 preferred solvent and dimethyl sulfoxide.
Step 1 preferable reaction temperature is 110~130 DEG C.
6~9h of step 1 preferred reaction time.
Step 1 refining solvent can be one or more selected from the following：Toluene, acetonitrile, acetone, ethyl acetate, four
Hydrogen furans, methylene chloride, isopropyl ether, n-butanol, methanol, ethyl alcohol, methyl tertiary butyl ether(MTBE).
The preferred refining solvent of step 1 is：Methanol, ethyl alcohol, n-butanol, acetone.
Solvent used in step 2 can be selected from the following one or more：Toluene, methanol, ethyl alcohol, acetonitrile, acetone,
Ethyl acetate, tetrahydrofuran, methylene chloride, isopropyl ether, n-butanol.
Step 2 preferred solvent is ethyl acetate.
The crystallization whipping temp of step 2 is -10~20 DEG C.
Reaction dissolvent used in step 3 be acetone, tetrahydrofuran, ether, ethyl alcohol, ethyl acetate, isopropanol, n-butanol,
Methyl tertiary butyl ether(MTBE), butyl acetate, ethyl acetate.
Step 3 preferred solvent is tetrahydrofuran.
Refining solvent used in step 3 is n-butanol, acetone.
Example is embodied
The present invention is further illustrated combined with specific embodiments below, but scope of protection of the present invention is not limited thereto.
Example 1
The preparation of compound III：Compound I (50.0g, 0.3mol), dimethyl sulfoxide are sequentially added to 500mL there-necked flask
(AR, 250mL), potassium hydroxide (84.9g, 1.5mol), heating stirring, 120 DEG C of stirring 1h of temperature control, by compound II
（99.9g, 0.9mol）It is added drop-wise to reaction system, 120 DEG C of temperature control reactions, TLC monitors fully reacting, stops reaction.Reaction system
It is cooled to room temperature, to reaction system plus ethyl acetate 500mL and water 500ml, is sufficiently stirred and stands and separate organic phase, 1L washing
Twice, organic phase is dry with anhydrous sodium sulfate for organic phase, filters, collection filtrate to 3L single port bottle, addition oxalic acid (38.1g,
Ethyl acetate solution 1150mL 0.3mol), collected by suction filter cake, 40 DEG C of forced air dryings obtain off-white powder 88.5g, will consolidate
Body is dissolved in 885ml ethyl alcohol, is heated to reflux 1h, is down to room temperature and filters, and filter cake is obtained qualified products as 40 DEG C of forced air dryings
80.3g, yield 76.8%.
Example 2
The preparation of compound III：Compound I (5.0g, 0.03mol), dimethyl sulfoxide are sequentially added to 100mL there-necked flask
(AR, 25mL), potassium hydroxide (8.5g, 0.15mol), heating stirring, 130 DEG C of stirring 1h of temperature control, by compound II（10.0g,
0.09mol）It is added drop-wise to reaction system, continues 130 DEG C of temperature control reactions, TLC monitors fully reacting, stops reaction.Reaction system is cold
But room temperature is arrived, to reaction system plus ethyl acetate 50mL and water 50ml, is sufficiently stirred and stands and separate organic phase, 100ml washing
Twice, organic phase is dry with anhydrous sodium sulfate for organic phase, filters, collection filtrate to single port bottle, addition oxalic acid (3.8g,
Ethyl acetate solution 100mL 0.03mol), collected by suction filter cake, 40 DEG C of forced air dryings obtain off-white powder 8.5g, will consolidate
Body is dissolved in 85ml isopropanol, is heated to reflux 1h, is down to room temperature and filters, and filter cake is obtained qualified products as 40 DEG C of forced air dryings
7.6g, yield 72.7%.
Example 3
The preparation of compound IV：By compound III（77.0g, 22.3mmol）With 10% carbonic acid of 400ml ethyl acetate and 400ml
Potassium solution stirs dissolved clarification, collects organic phase, and organic phase is washed twice with 800ml, merges organic phase anhydrous sodium sulfate drying, takes out
Filter sloughs organic solvent and obtains yellow liquid, and mandelic acid is added to system under stirring condition（20.4g, 13.4mmol）Acetic acid
Ethyl ester solution 300mL, stirring to solid are precipitated, and filter, and collect filter cake and as 40 DEG C of air dry ovens.
By obtained solid ethyl acetate（Solid-liquid ratio=1:10）Be heated to reflux purifying 2 times, filter, by obtained solid as
40 DEG C of air dry ovens.Obtain the compound IV 25.4g for meeting optical purity, yield 28.0%.
Example 4
The preparation of compound V：Compounds Ⅳ is added into 100mL there-necked flask（5.0g, 12.3mmol）, it is used into 25ml acetic acid
Ethyl ester and 10% solution of potassium carbonate of 25ml stir dissolved clarification, collect organic phase, and organic phase is washed twice with 50ml, merge organic phase and use
Anhydrous sodium sulfate is dry, filters, sloughs organic solvent and obtain yellow liquid.Gained liquid is transferred to three mouthfuls with 25mL isopropanol
Bottle stirs dissolved clarification, is passed through hydrogen chloride gas to PH=1~2, and solid is precipitated, and depressurizes collected by suction filter cake, obtains white solid
2.6g, yield 72.6%.
Example 5
The purification of compound V：Compound V is added into 100mL there-necked flask（2.0g, 6.9mmol）, 20ml acetone is heated to
Return stirring 2h stops heating, is cooled to and crystallization 2h is stirred at room temperature, and filters, and collects filter cake and as 40 DEG C of air dry ovens, obtains
To white solid 1.8g, yield 90.0%, N- methyl -3- phenoxy group-amphetamine 0.15%.
Claims (9)
1. the preparation method of tomoxetine hydrochloride as follows obtains intermediate with compound I and compound II substitution reaction
Compound III, compound III obtain R configuration intermediate compound IV by fractionation, obtain finished product hydrochloric acid support at salt with hydrogen chloride gas
Moses spit of fland, process impurity N- methyl -3- phenoxy group-amphetamine limit handling 0.2% hereinafter, effective guarantee drug quality, specifically
Route is as follows：
。
2. the synthesis technology of tomoxetine hydrochloride according to claim 1, wherein step 1 compound I and compound II
Substitution reaction, be the processing step that N- methyl -3- phenoxy group-amphetamine generates.
3. being 110~130 DEG C according to step 1 reaction temperature described in claims 1 and claims 2.
4. according to 6~9h of step 1 reaction time described in claims 1 and claims 2.
5. can be according to refining solvent used in compound III described in claims 1 and claims 2 selected from the following
It is one or more：Toluene, methanol, ethyl alcohol, acetonitrile, acetone, ethyl acetate, tetrahydrofuran, methylene chloride, isopropyl ether, n-butanol.
6. preferred according to refining solvent used in compound III described in claims 1 and claims 5：Methanol, ethyl alcohol,
N-butanol, acetone.
7. being -10~20 DEG C according to the crystallization whipping temp of step 2 described in claims 1 and claims 2.
8. stating refining solvent used in compound IV according to claims 1 and claims 2 can be selected from following
It is one or more：Toluene, methanol, ethyl alcohol, acetonitrile, acetone, ethyl acetate, tetrahydrofuran, methylene chloride, isopropyl ether, positive fourth
Alcohol.
9. according to the preferred n-butanol of refining solvent, acetone used in compound IV described in claims 1 and claims 8.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710382278.3A CN108929236A (en) | 2017-05-26 | 2017-05-26 | The preparation of tomoxetine hydrochloride |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710382278.3A CN108929236A (en) | 2017-05-26 | 2017-05-26 | The preparation of tomoxetine hydrochloride |
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| CN108929236A true CN108929236A (en) | 2018-12-04 |
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| CN201710382278.3A Pending CN108929236A (en) | 2017-05-26 | 2017-05-26 | The preparation of tomoxetine hydrochloride |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113527114A (en) * | 2021-06-15 | 2021-10-22 | 海南卓科制药有限公司 | Preparation method of tomoxetine hydrochloride |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6541668B1 (en) * | 1999-04-09 | 2003-04-01 | Eli Lilly And Company | Methods for preparing 3-arloxy-3-arylpropylamines and intermediates thereof |
| US20060009489A1 (en) * | 2004-06-28 | 2006-01-12 | Eugenio Castelli | Process for the preparation of atomoxetine hydrochloride |
| WO2006009884A1 (en) * | 2004-06-17 | 2006-01-26 | Dr. Reddy's Laboratories Ltd. | 3-aryloxy-3-arylpropylamine synthesis |
| CN1891682A (en) * | 2005-07-04 | 2007-01-10 | 上海华理生物医药有限公司 | Method for preparing 3-aryloxy-3-aryl propylamine |
| US20080004470A1 (en) * | 2004-09-27 | 2008-01-03 | Mathad Vijayavitthal T | Synthesis of Atomoxetine Hydrochloride |
| WO2008062473A1 (en) * | 2006-10-31 | 2008-05-29 | Cadila Healthcare Limited | Process for preparing atomoxetine hydrochloride |
| US20160107983A1 (en) * | 2013-07-02 | 2016-04-21 | Zcl Chemicals Limited | An improved process for the preparation of 3-aryloxy-3-phenylpropylamine and salt thereof |
| CN106187788A (en) * | 2016-07-29 | 2016-12-07 | 北京万全德众医药生物技术有限公司 | A kind of preparation method of tomoxetine hydrochloride |
-
2017
- 2017-05-26 CN CN201710382278.3A patent/CN108929236A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6541668B1 (en) * | 1999-04-09 | 2003-04-01 | Eli Lilly And Company | Methods for preparing 3-arloxy-3-arylpropylamines and intermediates thereof |
| WO2006009884A1 (en) * | 2004-06-17 | 2006-01-26 | Dr. Reddy's Laboratories Ltd. | 3-aryloxy-3-arylpropylamine synthesis |
| US20060009489A1 (en) * | 2004-06-28 | 2006-01-12 | Eugenio Castelli | Process for the preparation of atomoxetine hydrochloride |
| US20080004470A1 (en) * | 2004-09-27 | 2008-01-03 | Mathad Vijayavitthal T | Synthesis of Atomoxetine Hydrochloride |
| CN1891682A (en) * | 2005-07-04 | 2007-01-10 | 上海华理生物医药有限公司 | Method for preparing 3-aryloxy-3-aryl propylamine |
| WO2008062473A1 (en) * | 2006-10-31 | 2008-05-29 | Cadila Healthcare Limited | Process for preparing atomoxetine hydrochloride |
| US20160107983A1 (en) * | 2013-07-02 | 2016-04-21 | Zcl Chemicals Limited | An improved process for the preparation of 3-aryloxy-3-phenylpropylamine and salt thereof |
| CN106187788A (en) * | 2016-07-29 | 2016-12-07 | 北京万全德众医药生物技术有限公司 | A kind of preparation method of tomoxetine hydrochloride |
Non-Patent Citations (1)
| Title |
|---|
| 徐克勋: "《精细有机化工原料及中间体手册》", 30 June 1998, pages: 3 - 458 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113527114A (en) * | 2021-06-15 | 2021-10-22 | 海南卓科制药有限公司 | Preparation method of tomoxetine hydrochloride |
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