CN105949142B - Single chiral compound with antidepressant activity and its preparation method and application - Google Patents
Single chiral compound with antidepressant activity and its preparation method and application Download PDFInfo
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- CN105949142B CN105949142B CN201610341208.9A CN201610341208A CN105949142B CN 105949142 B CN105949142 B CN 105949142B CN 201610341208 A CN201610341208 A CN 201610341208A CN 105949142 B CN105949142 B CN 105949142B
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- chiral compound
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
- C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
Abstract
A kind of single chiral compound with antidepressant activity and its preparation method and application, is related to pharmaceutical chemistry technical field, and its structural formula is：The structure of the compound is different from existing antidepressant compounds, has brand-new molecular structure, while the compound also has good antidepressant activity.
Description
Technical field
The present invention relates to pharmaceutical chemistry technical field, more particularly to a kind of single chiral compound with antidepressant activity
And its preparation method and application.
Background technology
Depression is a kind of potential, mental disorder of being in peril of one's life property, and it can bring huge spirit
Pressure, it can cause to commit suiside when serious.With society and economic fast development, the quickening of rhythm of life, the incidence of disease of depression
The trend risen year by year is showed, according to statistics, Chinese patients with depression is more than 26,000,000.Clinically, traditional antidepressants
Thing much all suffers from the problem of drug effect is low, action is slow, side effect is larger, is badly in need of developing new antidepressant.
After the medicine of chiral different (i.e. stereochemical structure is different) enters in organism, raw with enzyme, acceptor, ion channel etc.
In the presence of thing macromolecular, different pharmacokinetics behaviors may be shown.Early in 1992, U.S. FDA just disclosed
When it is racemic modification to develop medicine, it is necessary to the criterion studied respectively two kinds of enantiomters.At the beginning of 21 century, almost
All chiral synthetic drugs are listed in the form of individual isomer.The acquisition of chiral drug is always medicament research and development
Difficult point and hot issue, medicine scholar are not stopping the how easy acquisition pure pharmaceutical methods of single chiral of research for many years.
The content of the invention
Novel and with good antidepressant activity the single hand the technical problem to be solved in the present invention is to provide a kind of structure
Property compound.In addition, the present invention also provides the preparation method and purposes of above-mentioned single chiral compound.
In order to solve the above-mentioned technical problem, the present invention adopts the following technical scheme that：It is a kind of single with antidepressant activity
Chipal compounds, its structural formula are：
As another aspect of the present invention, the application of the above-mentioned single chiral compound with antidepressant activity is included it
As a kind of raw material for preparing new antidepressant.
As another aspect of the present invention, the method for preparing the above-mentioned single chiral compound with antidepressant activity, bag
Include following steps：
The first step, the bromo- acetone of 1- (m-trifluoromethylphenyl) -2-, NMP and (R) -2- aminopropanols is taken to make reactive component,
Course of reaction oxygen barrier and reaction temperature control at 35-65 DEG C；
Second step, regulation reacting liquid pH value to alkalescence, absolute ether stirring is added, then stratification, is isolated afterwards
Organic layer；
3rd step, HCl gases are passed through under conditions of less than 30 DEG C, obtain white solid.
Wherein, the bromo- acetone of 1- (m-trifluoromethylphenyl) -2-, NMP and (the R) -2- aminopropanols used in the first step
Mol ratio is 0.01：0.363：0.04.
Wherein, reaction temperature is controlled at 53 DEG C in the first step.
Preferably, first the bromo- acetone of 1- (m-trifluoromethylphenyl) -2- and NMP magnetic agitations are well mixed in the first step,
Then (R) -2- aminopropanols are added to be reacted.
Preferably, protected in the first step using nitrogen, so as to realize course of reaction oxygen barrier.
It is also preferred that ice bath cooling first is carried out to it before reacting liquid pH value to alkalescence is adjusted.
It is also preferred that reacting liquid pH value is adjusted to alkalescence using saturated sodium carbonate solution in second step.
Preferably, first it is dried using anhydrous sodium sulfate after isolating organic layer, carried out again after filtering out drier
3rd step, it is preferred that ice bath cooling first is carried out to the organic layer separated before the 3rd step is carried out, HCl is passed through in the 3rd step
Preferably constantly isolated organic layer is stirred while gas, it is also preferred that using suction filtration mode in second step
Organic layer is isolated, filtrate is extracted using absolute ether.
The beneficial effect that the present invention obtains is：The present invention provides a kind of new outside existing antidepressant compounds
Single chiral compound, the structure of the single chiral compound is different from existing antidepressant compounds, has brand-new molecule
Structure, meanwhile, it the experiment proved that, the single chiral compound has good antidepressant activity.In addition, in the present invention, system
Compared with the conventional method, its step is simple, easy to operate for the method for standby above-mentioned single chiral compound, should suitable for industrial production
With.
Brief description of the drawings：
Fig. 1 is the crystal structure figure of compound in the present invention.
Embodiment
For the ease of the understanding of those skilled in the art, the present invention is made with reference to specific embodiments and the drawings further
Explanation, the content that embodiment refers to not is limitation of the invention.
First, the preparation of noval chemical compound：
The bromo- acetone 2.8107g (0.01mol) of 1- (m-trifluoromethylphenyl) -2- and NMP35ml (0.363mol) is taken to add
Reaction vessel, after magnetic agitation is uniform, add (R) -2- aminopropanols 3.0044g (0.04mol), nitrogen protection, heated for controlling temperature
To 53 DEG C of reaction 1h, ice bath cooling, add saturated sodium carbonate solution and adjust pH value to alkalescence, add absolute ether 40ml, stirring
After several minutes, stratification, filter, filtrate is extracted with absolute ether (20ml × 3), and organic layer is washed with distilled water (20ml × 3)
Wash, collected organic layer, with anhydrous sodium sulfate drying, filter out drier, ice bath cooling, stirring, be slowly introducing dry HCl gases,
Untill white solid no longer increases, white solid is filtered out, then washs obtained white solid with acetone, finally drying is
It can obtain the noval chemical compound.
It should be noted that in above-mentioned preparation process, the bromo- acetone of 1- (m-trifluoromethylphenyl) -2-, NMP and (R) -
2- aminopropanols can also add reaction vessel simultaneously, and above-mentioned 3 kinds of reactive components use the reason for matching above mainly to consider most
The yield issues of whole compound, do not represent each component when preparing the noval chemical compound and have to use said ratio.In addition, anti-
During answering, nitrogen protection is not unique oxygen barrier guard method, it will be appreciated by those skilled in the art that, it can also use existing
Other oxygen isolation methods in technology, can be adjusted correspondingly according to yield and reaction time as reaction temperature, preferably exist
In the range of 35-65 DEG C, reaction temperature, which is set in outside above range, certainly finally can also obtain a certain amount of noval chemical compound, but
It is the problem of this would be possible to cause yield to reduce and the reaction time increases.May be used also in addition, reacting liquid pH value is adjusted to alkalescence
Can be selected as needed in the prior art using other materials in addition to saturated sodium carbonate solution, those skilled in the art
The pH value of reaction solution is adjusted other strong base-weak acid salts.Last those skilled in the art are also apparent that whole
In preparation process, even if omitting the dry step of above-mentioned ice bath cooling and washing, it finally also can obtain the present embodiment to be prepared
Noval chemical compound, certainly, dry if not carrying out washing on white solid in preparation process and will influence the compound that finally gives
Purity.
Above-mentioned preparation process can be used to lower reaction equation and represent：
After measured, its molecular formula of the noval chemical compound being finally prepared is：C13H17NO2F3Cl molecular weight is:311.5, melt
Put and be：235~237 DEG C, structural formula is：
Structured data is：1H NMR (DMSO-D6), δ：0.95~0.97 (d, 3H, CH3), 1.22~1.24 (d, 3H,
CH3), 3.46 (m, 1H, morpholine ring 5-H), 3.86 (m, 1H, morpholine ring 3-H), 3.88~3.91 (m, 2H, morpholine ring 6-H),
7.65~7.68 (m, 2H, phenyl ring-H), 7.77~7.80 (d, 1H, OH), 7.85~7.87 (d, 2H, phenyl ring-H), 8.81 (s,
1H, NH), 10.25 (br s, 1H, HCl)；IR(KBr),ν,cm-1:3213,2945,2791,1571,1552,1444,1408,
1334,1249,1112,1060,1001,912,817,709,653；MS(m/z)：276.2(M+1- HCl), 258.2 (M+1-HCl-
H2O)。
Crystal structural data is：
As shown in Figure 1, compound name is compound crystal structure chart：(2S, 3S, 5R) -3,5- dimethyl -2- (3- tri-
Trifluoromethylphenyl) -2- morpholine alcohol hydrochlorides.
From said determination result it was determined that the white solid that above-mentioned preparation process finally gives be one kind between existing
The single chiral compound with brand-new molecular structure outside antidepressant compounds.
2nd, the antidepressant activity identification of noval chemical compound：
The present invention carries out antidepressant activity identification using mouse forced swimming test pharmacological evaluation to noval chemical compound.
In mouse forced swimming test model, mouse is forced in the space swimming of a limitation, and they struggle first makes an attempt at escaping,
Then in a kind of motionless state, this state is referred to as " behavioral despair ".Most antidepressants can subtract in this model
The dead time (time i.e. in behavioral despair state) of few animal, and its drug effect in an experiment and clinically drug effect are notable
It is related.
Mouse forced swimming test pharmacological evaluation：
1st, experimental animal：Body weight 20-24g Kunming male white mouse (80).21-23 DEG C of raising temperature, by University Of Nanhua
Animal Experimental provides, production licence number：SCXK (Hunan) 2015-0002, animal quality certification number：Move (matter) 95013 in Hunan
2nd, 2, the medicine of experiment：Positive controls medicine：Prozac；Ma Nifaxin；Test group：The compounds of this invention (2S,
3S, 5R) -3,5- dimethyl -2- (3- trifluoromethyls) -2- morpholines alcohol hydrochlorides and its enantiomer (2R, 3R, 5S) -3,5-
Dimethyl -2- (3- trifluoromethyls) -2- morpholine alcohol hydrochlorides.
3rd, experiment material：Large beaker 6 (diameter 14cm, high 20cm), 1, thermometer, 6, stopwatch, electronic balance 1,
Irrigation stomach device 1, thermostat water bath 1.
4th, animal packet：10 groups of blank control (every group 2, physiological saline)；20 groups of positive control (every group 2, fluorine west
Spit of fland, Ma Nifaxin)；Fractions tested is 10 groups (every group 2)；Test group 2 is divided for 10 groups (every group 2).
5th, administering mode：The compound tested is by 50mgkg-1Enter medicine, 30min progress gavage enters medicine before experiment.It is real
12h fasting, can't help water, natural lighting, raising temperature (22 ± 2) DEG C before testing.
6th, experimental method：Mouse after administration is put into high 20cm, in diameter 14cm beaker, depth of water 10cm is each to burn
Cup puts a mouse, water temperature (25 ± 1) DEG C, and during experiment, mouse is accumulative not in 4min after cup went swimming about 6min, record for mouse
The dynamic time, water need to be changed by having recorded tests again.
7th, the motionless behavior of mouse judges：Mouse stop in water struggle, in swim in water or only tiny limbs transport
Move to keep head to float on the surface.
Finally give that the experimental results are shown inthe following table：
, single chiral compound of the invention compared with positive drug group and control group, measurement data with x pull out (average) ±
S is represented, is examined with t, is statistically analyzed rear P ＜ 0.05, difference is statistically significant.Mouse forced swimming test pharmacological evaluation table
Bright, it is 50mgkg that the single chiral compound, which enters dose,-1Mouse forced swimming test quiescent time is 47 ± 20, hence it is evident that less than blank
Control group mice forced swimming quiescent time 150 ± 48, also enter dose significantly lower than positive drug Fluaxetine (Fluoxetine)
For 50mgkg-1Mouse forced swimming test quiescent time 84 ± 36, with antidepression positive control medicine Ma Nifaxin
(Manifaxine) mouse forced swimming test quiescent time 47 ± 20 is suitable, meanwhile, the compounds of this invention mouse forced swimming test is static
Time is significantly lower than its enantiomer (2R, 3R, 5S) -3,5- dimethyl -2- (3- trifluoromethyls) -2- morpholine alcohol hydrochlorides,
Therefore, single chiral compound of the invention has good antidepressant activity.
Above-described embodiment is the preferable implementation of the present invention, and in addition, the present invention can be realized with other manner,
Any obviously replaced on the premise of not departing from the technical program design within protection scope of the present invention.
Finally it should be emphasised that in order to allow those of ordinary skill in the art more easily to understand the present invention relative to existing
There are the improvements of technology, some descriptions of the invention have been simplified, and for the sake of clarity, present specification is also omitted
Some other elements, those of ordinary skill in the art should be aware that these elements omitted also may make up the interior of the present invention
Hold.
Claims (13)
1. a kind of single chiral compound with antidepressant activity, its structural formula are：
2. application of the single chiral compound with antidepressant activity in antidepressant is prepared described in claim 1.
3. preparing the method for the single chiral compound with antidepressant activity described in claim 1, comprise the following steps：
The first step, 1- (m-trifluoromethylphenyl) -2- bromo- acetone, NMP and (R) -2- aminopropanols are taken as reactive component, instead
Answer process oxygen barrier and reaction temperature is controlled at 35-65 DEG C；
Second step, regulation reacting liquid pH value to alkalescence, absolute ether stirring is added, then stratification, is isolated organic afterwards
Layer；
3rd step, HCl gases are passed through under conditions of less than 30 DEG C, obtain white solid.
4. the single chiral compound with antidepressant activity according to claim 3 prepared described in claim 1
Method, it is characterised in that：The bromo- acetone of 1- (m-trifluoromethylphenyl) -2-, NMP and (the R) -2- aminopropans used in the first step
The mol ratio of alcohol is 0.01：0.363：0.04.
5. the single chiral compound with antidepressant activity described in the preparation claim 1 according to claim 3 or 4
Method, it is characterised in that：Reaction temperature control is at 53 DEG C in the first step.
6. the single chiral compound with antidepressant activity according to claim 5 prepared described in claim 1
Method, it is characterised in that：First the bromo- acetone of 1- (m-trifluoromethylphenyl) -2- and NMP magnetic agitations are mixed in the first step
It is even, then add (R) -2- aminopropanols and reacted.
7. the single chiral compound with antidepressant activity according to claim 5 prepared described in claim 1
Method, it is characterised in that：Protected in the first step using nitrogen, so as to realize course of reaction oxygen barrier.
8. the single chiral compound with antidepressant activity according to claim 5 prepared described in claim 1
Method, it is characterised in that：Ice bath cooling first is carried out to it before reacting liquid pH value to alkalescence is adjusted.
9. the single chiral compound with antidepressant activity according to claim 5 prepared described in claim 1
Method, it is characterised in that：Reacting liquid pH value is adjusted to alkalescence using saturated sodium carbonate solution in second step.
10. the single chiral compound with antidepressant activity according to claim 7 prepared described in claim 1
Method, it is characterised in that：First it is dried using anhydrous sodium sulfate after isolating organic layer, carried out again after filtering out drier
3rd step.
11. the single chiral compound with antidepressant activity according to claim 10 prepared described in claim 1
Method, it is characterised in that：Ice bath cooling first is carried out to isolated organic layer before the 3rd step is carried out.
12. the single chiral compound with antidepressant activity according to claim 11 prepared described in claim 1
Method, it is characterised in that：Constantly isolated organic layer is stirred while being passed through HCl gases in 3rd step.
13. the single chiral compound with antidepressant activity according to claim 12 prepared described in claim 1
Method, it is characterised in that：Organic layer is isolated using suction filtration mode in second step, filters the filter isolated and obtained after organic layer
Liquid is extracted using absolute ether.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5104870A (en) * | 1989-10-31 | 1992-04-14 | Burroughs Wellcome Co. | Heterocyclic pharmaceutical compounds and use |
| US5760224A (en) * | 1991-04-23 | 1998-06-02 | Glaxo Wellcome Inc. | Arylmorpholine preparation and use |
| CN1528753A (en) * | 1998-01-21 | 2004-09-15 | Morpholol with medicinal activity | |
| CN102548976A (en) * | 2009-08-31 | 2012-07-04 | 雅培卫生保健产品有限责任公司 | (Thio) morpholine derivatives as S1P modulators |
-
2016
- 2016-05-21 CN CN201610341208.9A patent/CN105949142B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5104870A (en) * | 1989-10-31 | 1992-04-14 | Burroughs Wellcome Co. | Heterocyclic pharmaceutical compounds and use |
| US5760224A (en) * | 1991-04-23 | 1998-06-02 | Glaxo Wellcome Inc. | Arylmorpholine preparation and use |
| CN1528753A (en) * | 1998-01-21 | 2004-09-15 | Morpholol with medicinal activity | |
| CN102548976A (en) * | 2009-08-31 | 2012-07-04 | 雅培卫生保健产品有限责任公司 | (Thio) morpholine derivatives as S1P modulators |
Non-Patent Citations (3)
| Title |
|---|
| 2-芳基-2-吗啉醇类化合物合成及生物活性研究;梁俊;《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》;20110515;第B016-67页 * |
| 手性3,5,-二甲基-2-芳基-2-吗啉醇盐酸盐的合成及其晶体结构;肖新荣等;《有机化学》;20071231;第27卷(第8期);第989-993页 * |
| 间二氟吗啉醇衍生物分子设计、合成及抗实验性抑郁活性研究;郑友霖等;《南华大学学报( 自然科学版)》;20141231;第28卷(第4期);第97-101页 * |
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