CN101412707A - Duloxetine derivative and preparation thereof - Google Patents
Duloxetine derivative and preparation thereof Download PDFInfo
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- CN101412707A CN101412707A CNA2008101535520A CN200810153552A CN101412707A CN 101412707 A CN101412707 A CN 101412707A CN A2008101535520 A CNA2008101535520 A CN A2008101535520A CN 200810153552 A CN200810153552 A CN 200810153552A CN 101412707 A CN101412707 A CN 101412707A
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- duloxetine
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Abstract
The invention relates to a duloxetine derivative and a method for preparing the same, which belongs to the chemistry field of medicine with antidepressant activity. The structural formula is as shown in the right formula, wherein R is aryl radical or tertiary butyl. The method for preparing the duloxetine derivative comprises the following steps: dissolving duloxetine in dichloromethane; adding an acid-binding agent into the mixture of which the mol ratio of the duloxetine to the acid-binding agent is between 1 to 1.5 and 1 to 3; stirring the mixture at room temperature for 20 minutes, and then dripping acyl chloride into the mixture of which the molar ratio of the duloxetine to the acyl chloride is between 1 to 1.2 and 1 to 2; reacting the mixture at a temperature of between 0 and 30 DEG C for 1 to 5 hours to obtain the duloxetine derivative, wherein the acid-binding agent is N, N-diisopropyl ethyl amine, pyridine or triethylamine, and the acyl chloride is aryl acyl chloride or pivalyl chloride. The duloxetine derivative prepared by the method has multiple mechanisms of action simultaneously, and can be used for preparing antidepressant drugs. Besides, the preparation process is simple and easy to operate.
Description
Technical field
The invention belongs to pharmaceutical chemistry field, relate to a kind of duloxetine derivative and preparation method with antidepressant activity.
Background technology
Dysthymia disorders is a kind of common mental disorder, belongs to affective disorder.The pathological change of depression relates generally to central nervous system function, personally discusses system function and neuroendocrine system function.Along with the progress and the expanding economy of society, human lives's rhythm is accelerated day by day, social competition be growing more intense cause people work and living pressure increasing, the sickness rate of depression increases just year by year.According to western countries' statistics, average per 20 philtrums just have 1 people to suffer from dysthymia disorders.And the sickness rate of global dysthymia disorders is about 3.1%, and dysthymia disorders has become the fourth-largest in the world common disease at present, and dysthymia disorders is just becoming serious global problems at present.
From last century the fifties first-generation antidepressant drug phenothiazines heterocycle (three ring Fourth Ring) class antidepressant drug has appearred, be called for short TCAs.The s-generation antidepressant drug that occurs to the eighties latter stage is selective serotonin reuptake inhibitor both, is called for short SSRIs.Arrive third generation thymoleptic such as NE/5-HT reuptake inhibitor SNRI (Venlaxine, Milnacipran, Duloxetine, appearance Nefazodone) again.Antidepressant drug has passed through significant progress, and antidepressant effect has had large increase.But the medicine of existing widespread use still exists side effect big, tolerance and poor stability, and curative effect is bad, deficiencies such as medicine lag-phase length.Therefore it is little to seek side effect, and quick acting is replied the novel antidepressant of speed preferably, becomes becoming increasingly conspicuous of task.
Thymoleptic by the exploitation of U.S. Eli Lilly company, duloxetine (N-methyl-3-(naphthalene-1-yloxy)-3-(thiophen-2-yl) propan-1-amine) is a third generation thymoleptic, and it has very strong restraining effect to serotonin and norepinephrine reuptake.Its clinical application is extensive, and chemical stability is good, and security is good.Structure activity study shows, though duloxetine is the same with fluoxetine is the aryloxypropylamines class formation, but fluoxetine is the substance mechanism of action, and duloxetine is a double action mechanism, and this is owing to the reason that has thiphene ring and naphthalene ring in the duloxetine simultaneously.This shows that structural subtle change can influence the mechanism of action of compound.Monge group is by SSRI (aryloxy propanol amine) and 5-HT
1AThe compound that the intramolecularly combination of receptor-blocking agent (aromatic piperazine) obtains is to 5-HT
1AAcceptor and 5-HT conducting band have higher affinity, might cause the discovery of the novel antidepressant of double action mechanism, and compound has been in and has goed deep into the development phase.Eli Lilly company has reported the compound that is combined by aromatic piperazine and Indolylpiperidine, and the result shows to have antidepressant activity preferably.Its pharmacologically acceptable salt of multiple compound is arranged in addition, solvate, the medicament thing and the prodrug that reach these salt are among the clinical experiment, have vast potential for future development.
Summary of the invention
The objective of the invention is at the side effect of thymoleptic such as current phenothiazines heterocycle, NE/5-HT reuptake inhibitor SNRI greatly, the deficiency that the medicine lag-phase is long provides a kind of duloxetine derivative and preparation method thereof.
Technical scheme of the present invention is:
A kind of duloxetine derivative is characterized in that structural formula is as follows:
Above described aromatic group be 4-aminomethyl phenyl, 4-vinyl toluene base, styryl, 4-methoxyl-styrene, 4-chloro-styrene base or 2-acetylphenyl.
The preparation method of above-mentioned duloxetine derivative, its preparation general formula is:
It is characterized in that may further comprise the steps:
Duloxetine is dissolved in the methylene dichloride, proportioning for the 0.01mol duloxetine with 30～45ml methylene dichloride, add acid binding agent then, its proportioning is mol ratio duloxetine: acid binding agent=1:1.5～3, stir after 20 minutes under the room temperature, splash into acyl chlorides again, its mol ratio is duloxetine: acyl chlorides=1:1.2～2, under 0～30 ℃, reacted 1～5 hour, extraction, drying and underpressure distillation obtain duloxetine derivative;
Wherein acid binding agent is N, N-diisopropyl ethyl amine, pyridine or triethylamine; Acyl chlorides is aromatic base acyl chlorides or trimethyl-acetyl chloride.
Above described aromatic base acyl chlorides be 4-methylbenzene acrylate chloride, 2-acetylbenzene formyl chloride, acryloyl chloride, 4-anisole acrylate chloride, 4-chlorobenzene third rare acyl chlorides or 4-methyl benzoyl chloride.
Beneficial effect of the present invention is:
This derivative can have multiple action mechanism simultaneously, can be used for preparing antidepressant drugs.And its preparation process is simple to operation.
Embodiment
Embodiment 1:4-methylbenzene acrylate chloride
Add in the there-necked flask 4-methylbenzene vinylformic acid (9.73g, 0.06mol) and 2 DMF, adding 100ml toluene is solvent, (temperature slowly is increased to 100 ℃ and refluxed 3 hours for 14.27g, 0.12mol) sulfur oxychloride in slowly dropping, decompression (vacuum tightness 10mmHg, following examples are together) to steam and remove toluene and excessive sulfur oxychloride, the oil pump underpressure distillation is collected 135-136 ℃/5mmHg component and is obtained white solid 10.29g, yield 95.0%.mp：60-62℃。
IR(KBr)v(cm
-1)：3085，2923，1741，1601，1510，806，771。
Embodiment 2:4-anisole acrylate chloride
Add in the there-necked flask 4-anisole vinylformic acid (21.38g, 0.12mol), the N-N dimethyl formamide (DMF) of catalytic amount, solvent toluene 160ml, slowly dripping thionyl chloride (28.55g, 0.24mol), temperature slowly is increased to 100 ℃ and refluxed 3 hours, removes toluene and excessive sulfur oxychloride under reduced pressure, and 144-145 ℃/2mmHg cut is collected in the oil pump underpressure distillation, get glassy yellow solid 22.28g, productive rate 93.942%.mp：40-44℃。
IR(KBr)v(cm
-1)：3052，2844，1688，1600，1514，862，775。
Embodiment 3:4-chlorobenzene acrylate chloride
Add 4-chlorobenzene vinylformic acid (18.20g in the there-necked flask, 0.10mol), the N-N dimethyl formamide (DMF) of catalytic amount, solvent toluene 100ml, slowly dripping thionyl chloride (23.80g, 0.2mol), temperature slowly is increased to 100 ℃ and refluxed 3 hours, and vacuum rotary steam removes toluene and excessive sulfur oxychloride, and 118-120 ℃/3mmHg cut is collected in the oil pump underpressure distillation, get white solid 19.30g, productive rate 96.55%.mp：61-63℃。IR(KBr)v(cm
-1)：3034，2970，1699，1592，1490，846，736。
Embodiment 4:
Add duloxetine (3.3g in the 100ml there-necked flask, 0.011mol) and methylene dichloride (40ml), add triethylamine (2.5ml, 0.018mol) stir under the room temperature 4-methylbenzene acrylate chloride that is added dropwise to gained among the embodiment 1 after 20 minutes (2.7g, 0.015mol) the stirring at room reaction is 2 hours, adds entry (50ml) after reaction finishes, use dichloromethane extraction, use 30ml at every turn, extract the organic phase anhydrous magnesium sulfate drying three times.Remove solvent under reduced pressure, (sherwood oil: ethyl acetate=3:1) get tawny jelly N-4-methylbenzene acryl-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine 3.05g, yield is 63% to column chromatography for separation.(R is: 4-vinyl toluene base)
1HNMR(400MHz，CDCl
3)δ：8.39-8.37(m，1H，-Nap-H)；7.80-7.77(m，1H，-Nap-H)；7.66-7.58(m，1H，＝
CH-Ar)；7.51-7.47(m，2H，-Ar-H)；7.41-7.27(m，2H，-Ar-H)；7.26-7.16(m，3H，-Ar-H)；7.12-7.11(m，1H，-
CH＝-Ar)；7.07-6.68(m，5H，-Ar-H)；5.75-5.73(m，1H，-O
CH)；3.91-3.10(m，5H，-N
CH 3 ，-COCH
2 CH 2)；2.57-2.2.42(m，2H，-OCH
CH 2 )；2.46-2.31(m，3H，Ar-CH
3)MS：m/s442(M+H
+)。
Embodiment 5
Change acid binding agent wherein into pyridine, the consumption of 4-methylbenzene acrylate chloride changes that (2.34g, 0.013mol), other reaction process are with embodiment 4 into.The gained target product yield is 55.1%.
Embodiment 6
Change acid binding agent wherein into N, the N-diisopropyl ethyl amine, other reaction process are with embodiment 4.The gained target product yield is 42%.
Embodiment 7
The consumption of 4-methylbenzene acrylate chloride is changed into (3.24g, 0.018mol), other reaction process are with embodiment 4.The gained target product yield is 65%.
Embodiment 8
The consumption of 4-methylbenzene acrylate chloride is changed into (4g, 0.022mol), other reaction process are with embodiment 4.The gained target product yield is 66.3%.
Embodiment 9:
Add duloxetine (3.3g in the 100ml there-necked flask, 0.011mol) and methylene dichloride (40ml), add triethylamine (2.5ml, 0.018mol) stir under the room temperature be added dropwise to after 20 minutes trimethyl-acetyl chloride (2g, 0.167mol) the stirring at room reaction is 3 hours, adds entry (50ml) after reaction finishes, come together with methylene dichloride, each 30ml extracts the organic phase anhydrous magnesium sulfate drying 3 times.Remove solvent under reduced pressure, (sherwood oil: ethyl acetate=3:1) get tawny jelly N-4-pivaloyl-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine 2.74g, yield is 74% to column chromatography for separation.(R is: the tertiary butyl)
1HNMR(400MHz，CDCl
3)δ：8.28-8.26(m，1H，-Nap-H)；7.70-7.69(m，1H，-Nap-H)；7.43-7.7.39(m，2H，-Ar-H)；7.34-6.73(m，6H，-Ar-H)；5.63-5.60(m，1H，-O
CH)；3.66-2.97(m，5H，-N
CH 3 ，-COCH
2 CH 2 )；2.41-2.25(m，2H，-OCH
CH 2)；1.15(m，9H，-(
CH 3)
3).MS：m/s(ESI)372(M+1)
Embodiment 10:
Add duloxetine (4.05g in the 100ml there-necked flask; 0.0136mol) and methylene dichloride (60ml); add triethylamine (2.85ml; 0.02mol) stir after 20 minutes under the room temperature and be added dropwise to 2-acetylbenzene formyl chloride, stirring at room reaction 4.5 hours adds entry (50ml) after reaction finishes; use dichloromethane extraction; use 30ml at every turn, extract the organic phase anhydrous magnesium sulfate drying 3 times.Remove solvent under reduced pressure, (sherwood oil: ethyl acetate=3:1) get tawny jelly N-4-(2-acetylbenzene formyl radical)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine 2.94g, yield is 47% to column chromatography for separation.(R is: the 2-acetylphenyl)
Embodiment 11:
Add duloxetine (3.3g in the 100ml there-necked flask, 0.011mol) and methylene dichloride (50ml), add triethylamine (2.5ml, 0.018mol) stir under the room temperature be added dropwise to after 20 minutes acryloyl chloride (2.5g, 0.015mol) the stirring at room reaction is 3.5 hours, adds entry (50ml) after reaction finishes, use dichloromethane extraction, use 30ml at every turn, extract the organic phase anhydrous magnesium sulfate drying 3 times.Remove solvent under reduced pressure, (sherwood oil: ethyl acetate=3:1) get tawny jelly N-phenylpropenoyl-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine 2.60g, yield is 56% to column chromatography for separation.(R is: styryl)
1HNMR(400MHz，CDCl
3)δ：8.40-8.37(m，1H，-Nap-H)；7.80-7.77(m，1H，-Nap-H)；7.64-7.60(m，1H，＝
CH-Ar)；7.50-7.49(m，3H，-Ar-H)；7.40-7.34(m，2H，-Ar-H)；7.27-7.11(m，6H，-Ar-H)；7.09-7.07(m，1H，-
CH＝-Ar)；6.95-6.72(m，2H，-Ar-H)；5.76-5.73(m，1H，-O
CH)；3.98-3.10(m，5H，-N
CH 3，-COCH
2 CH 2)；2.57-2.2.42(m，2H，-OCH
CH 2).MS：m/s(ESI)428(M+H
+)。
Embodiment 12:
Add duloxetine (3.3g in the 100ml there-necked flask, 0.011mol) and methylene dichloride (50ml), add triethylamine (2.5ml, 0.018mol) stir under the room temperature 4-anisole acrylate chloride that is added dropwise to embodiment 2 gained after 20 minutes (2.8g, 0.015mol) the stirring at room reaction is 3.5 hours, adds entry (50ml) after reaction finishes, use dichloromethane extraction, use 30ml at every turn, extract the organic phase anhydrous magnesium sulfate drying 3 times.Remove solvent under reduced pressure, (sherwood oil: ethyl acetate=3:1) get tawny jelly N-4-anisole acryl-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine 1.7g, yield is 35% to column chromatography for separation.(R is: the 4-methoxyl-styrene)
Embodiment 13:
Add duloxetine (3.3g in the 100ml there-necked flask, 0.011mol) and methylene dichloride (50ml), add triethylamine (2.5ml, 0.018mol) stir under the room temperature 4-chlorobenzene acrylate chloride that is added dropwise to embodiment 3 gained after 20 minutes (2.8g, 0.015mol) the stirring at room reaction is 3.5 hours, adds entry (50ml) after reaction finishes, use dichloromethane extraction, use 30ml at every turn, extract the organic phase anhydrous magnesium sulfate drying 3 times.Remove solvent under reduced pressure, (sherwood oil: ethyl acetate=3:1) get tawny jelly N-4-chlorobenzene acryl-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine 1.93g, yield is 38% to column chromatography for separation.(R is: 4-chloro-styrene base)
Embodiment 14:
Add duloxetine (3.3g in the 100ml there-necked flask, 0.011mol) and methylene dichloride (50ml), add triethylamine (2.5ml, 0.018mol) stir under the room temperature be added dropwise to after 20 minutes the 4-methyl benzoyl chloride (2.4g, 0.0154mol) the stirring at room reaction is 3 hours, adds entry (50ml) after reaction finishes, use dichloromethane extraction, use 30ml at every turn, extract the organic phase anhydrous magnesium sulfate drying 3 times.Remove solvent under reduced pressure, (sherwood oil: ethyl acetate=3:1) get tawny jelly N-4-methyl benzoyl-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine 3.28g, yield is 72% to column chromatography for separation.(R is: the 4-aminomethyl phenyl)
1HNMR(400MHz，CDCl
3)δ：8.30(m，1H，-Nap-H)，7.90-7.84(m，1H，-Nap-H)；7.69-7.68(m，2H，-Ar-H)，7.41-7.36(m，2H，-Ar-H)；7.34-6.81(m，8H，-Ar-H)，5.73-5.66(m，1H，-O
CH)；3.81-2.47(m，5H，-
CH 2 N
CH 3，-COCH
2 CH 2)，2.45-2.34(m，3H，-CH
3)，2.30-2.04(m，2H，-OCH
CH 2).
MSm/s(ESI)：119.0(14)，161.8(10)，272.0(100)，416(M+1，79)。
Claims (4)
1, a kind of duloxetine derivative is characterized in that structural formula is as follows:
R is the aromatic group or the tertiary butyl.
2, as duloxetine derivative in the claim 1, it is characterized in that described aromatic group is 4-aminomethyl phenyl, 4-vinyl toluene base, styryl, 4-methoxyl-styrene, 4-chloro-styrene base or 2-acetylphenyl.
3, as the preparation method of duloxetine derivative in the claim 1, it is characterized in that may further comprise the steps:
Duloxetine is dissolved in the methylene dichloride, proportioning for the 0.01mol duloxetine with 30～45ml methylene dichloride, add acid binding agent then, its proportioning is mol ratio duloxetine: acid binding agent=1:1.5～3, stir after 20 minutes under the room temperature, splash into acyl chlorides again, its mol ratio is duloxetine: acyl chlorides=1:1.2～2, under 0～30 ℃, reacted 1～5 hour, extraction, drying and underpressure distillation obtain duloxetine derivative;
Wherein acid binding agent is N, N-diisopropyl ethyl amine, pyridine or triethylamine; Acyl chlorides is aromatic base acyl chlorides or trimethyl-acetyl chloride.
4; as the preparation method of duloxetine derivative in the claim 3, it is characterized in that described aromatic base acyl chlorides is 4-methylbenzene acrylate chloride, 2-acetylbenzene formyl chloride, acryloyl chloride, 4-anisole acrylate chloride, 4-chlorobenzene third rare acyl chlorides or 4-methyl benzoyl chloride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008101535520A CN101412707A (en) | 2008-11-27 | 2008-11-27 | Duloxetine derivative and preparation thereof |
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|---|---|---|---|
| CNA2008101535520A CN101412707A (en) | 2008-11-27 | 2008-11-27 | Duloxetine derivative and preparation thereof |
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| Publication Number | Publication Date |
|---|---|
| CN101412707A true CN101412707A (en) | 2009-04-22 |
Family
ID=40593474
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|---|---|---|---|
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012176621A1 (en) * | 2011-06-24 | 2012-12-27 | 株式会社ダイセル | Method for producing unsaturated carboxylic acid amide composition |
| CN110627766A (en) * | 2018-06-25 | 2019-12-31 | 江阴安博生物医药有限公司 | Novel duloxetine analogue, and preparation method and application thereof |
-
2008
- 2008-11-27 CN CNA2008101535520A patent/CN101412707A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012176621A1 (en) * | 2011-06-24 | 2012-12-27 | 株式会社ダイセル | Method for producing unsaturated carboxylic acid amide composition |
| JP2013006795A (en) * | 2011-06-24 | 2013-01-10 | Daicel Corp | Method for producing unsaturated carboxylic amide composition |
| CN110627766A (en) * | 2018-06-25 | 2019-12-31 | 江阴安博生物医药有限公司 | Novel duloxetine analogue, and preparation method and application thereof |
| CN110627766B (en) * | 2018-06-25 | 2023-12-29 | 北京安博睿达医药科技有限公司 | New duloxetine analogue, and preparation method and application thereof |
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Application publication date: 20090422 |