CN108707112A - A kind of preparation method of antidepressant agents impurity isomers chlorine nitre phenyl intermediates - Google Patents
A kind of preparation method of antidepressant agents impurity isomers chlorine nitre phenyl intermediates Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
- C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
- C07D223/24—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom
- C07D223/28—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom having a single bond between positions 10 and 11
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Abstract
The present invention relates to a kind of preparation methods of antidepressant agents impurity isomers chlorine nitre phenyl intermediates, it includes the following steps：（a）Sodium metaperiodate, water and DMF are mixed, the DMF solution that the compound 2 is then added is reacted, and filtrate is taken to purify to obtain compound 3 after reaction；（b）The bromo- 4- chlorotoluenes of 2-, N-bromosuccinimide, dibenzoyl peroxide and carbon tetrachloride are mixed, stirs and rises to 80 ~ 100 DEG C and reacted；It is then poured into ice water, pH is adjusted with lye and is layered extraction, purify to obtain compound 4；（c）The compound 3 and the compound 5 are added in glycol dimethyl ether, sodium hydride is added under conditions of ice-water bath, 40 ~ 60 DEG C is warming up to and reacts 20 ~ 40 minutes, then temperature rising reflux；It is 1 that volume ratio is added after reaction:1 water and ethyl acetate makes solid be precipitated, filters, dry compound 6.The high nitre phenyl intermediates of purity can be obtained in this way, for the preparation of follow-up high-purity and high yield antidepressant agents impurity isomers.
Description
Technical field
The invention belongs to medicine intermediate fields, are related to a kind of preparation method of antidepressant agents impurity isomers, specifically
It is related to a kind of preparation method of antidepressant agents impurity isomers chlorine nitre phenyl intermediates.
Background technology
Chlorimipramine (also known as Chlorimiopramine, Chlorimiopramine) alias, chemical formula C19H23ClN2, it is a kind of whitening color or micro- Huang
The chemicals of color can be used for making the various depressive states of drug therapy.Chlorimipramine is tricyclic antidepressant, main function
It is to block the reuptake of central nervous system norepinephrine and serotonin, the blocking of the reuptake of serotonin is made
With stronger, and antidepression and angst resistance effect are played, also there is calm and anticholinergic effect；For treating various depressive states,
It is also commonly used for treatment obsessive-compulsive neurosis, phobic neurosis.
(Me is methyl in formula) is impurity isomery important in chlorimipramine preparation process
Body needs to redesign synthetic route and determines that it prepares intermediate to obtain the impurity isomers of high-purity and yield.
Invention content
A kind of antidepressant agents impurity isomers chlorine nitre is provided the invention aims to overcome the deficiencies in the prior art
The preparation method of phenyl intermediates.
In order to achieve the above objectives, the technical solution adopted by the present invention is：A kind of antidepressant agents impurity isomers chlorine nitre benzene
The preparation method of base intermediate, it includes the following steps：
(a) 2- nitro -4- chlorotoluenes, N,N-dimethylformamide and N,N-dimethylformamide dimethylacetal are carried out
The DMF solution that 120~170 DEG C of progress back flow reactions obtain compound 2 is stirred and is risen in mixing；By sodium metaperiodate, water and DMF into
Row mixing, the DMF solution that the compound 2 is then added are reacted, and filtrate is taken to purify to obtain compound 3 after reaction；
(b) the bromo- 4- chlorotoluenes of 2-, N-bromosuccinimide, dibenzoyl peroxide and carbon tetrachloride are mixed,
It stirs and rises to 80~100 DEG C and reacted；It is then poured into ice water, pH is adjusted with lye and is layered extraction, purify to obtain chemical combination
Object 4；The compound 4 and triethyl phosphite are mixed again, column chromatography for separation obtains chemical combination after being reacted at 120~150 DEG C
Object 5；
(c) compound 3 and the compound 5 are added in glycol dimethyl ether, are added under conditions of ice-water bath
Sodium hydride is warming up to 40~60 DEG C and reacts 20~40 minutes, then temperature rising reflux；It is 1 that volume ratio is added after reaction:1 water
And ethyl acetate, so that solid is precipitated, filter, dry compound 6.
Optimally, in step (a), be added the compound 2 DMF solution reacted after, filtered, filter cake first
Benzene mashing is washed repeatedly, and to be layered, water phase toluene extracts at least once merging filtrate, merges organic phase and simultaneously washes repeatedly, with
It is spin-dried for afterwards with drying after saturated common salt water washing, column chromatography purifies to obtain the compound 3.
Optimally, in step (b), merge organic phase after layering extraction, the sodium bicarbonate solution for being 5% with mass fraction is washed
It washs, is spin-dried for after dry, carry out column chromatography for separation and obtain the compound 4.
Optimally, step (a) and step (b) be in no particular order.
Since above-mentioned technical proposal is used, the present invention has following advantages compared with prior art：Depression medicine of the present invention
The preparation method of object impurity isomers chlorine nitre phenyl intermediates successively obtains compound 3, change by redesigning synthetic route
Object 4 and compound 5 are closed, the high nitre phenyl intermediates of purity can be obtained in this way, it is for follow-up high-purity and depressed in high yield
The preparation of disease drug impurity isomers.
Description of the drawings
Attached drawing 1 is the synthetic route of the preparation method of antidepressant agents impurity isomers chlorine nitre phenyl intermediates of the present invention
Figure；
Attached drawing 2 is 3 core of compound in the preparation method of antidepressant agents impurity isomers chlorine nitre phenyl intermediates of the present invention
Magnetic spectrum figure；
Attached drawing 3 is 4 core of compound in the preparation method of antidepressant agents impurity isomers chlorine nitre phenyl intermediates of the present invention
Magnetic spectrum figure；
Attached drawing 4 is 5 core of compound in the preparation method of antidepressant agents impurity isomers chlorine nitre phenyl intermediates of the present invention
Magnetic spectrum figure；
Attached drawing 5 is 6 core of compound in the preparation method of antidepressant agents impurity isomers chlorine nitre phenyl intermediates of the present invention
Magnetic spectrum figure；
Attached drawing 6 is 10 nuclear magnetic spectrogram of compound in the preparation method of antidepressant agents impurity isomers of the present invention；
Attached drawing 7 be antidepressant agents impurity isomers of the present invention preparation method in final product nuclear magnetic spectrogram.
Specific implementation mode
The preparation method of antidepressant agents impurity isomers chlorine nitre phenyl intermediates of the present invention, it includes the following steps：(a)
2- nitro -4- chlorotoluenes, n,N-Dimethylformamide and n,N-Dimethylformamide dimethylacetal are mixed, stirring is simultaneously
It rises to 120~170 DEG C and carries out the DMF solution that back flow reaction obtains compound 2；Sodium metaperiodate, water and DMF are mixed, then
The DMF solution that the compound 2 is added is reacted, and filtrate is taken to purify to obtain compound 3 after reaction；(b) by the bromo- 4- chloromethanes of 2-
Benzene, N-bromosuccinimide, dibenzoyl peroxide and carbon tetrachloride are mixed, and are stirred and are risen to 80~100 DEG C of progress
Reaction；It is then poured into ice water, pH is adjusted with lye and is layered extraction, purify to obtain compound 4；Again by the compound 4 and Asia
Triethyl phosphate is mixed, and column chromatography for separation obtains compound 5 after being reacted at 120~150 DEG C；(c) by the compound 3 and institute
State compound 5 be added glycol dimethyl ether in, sodium hydride is added under conditions of ice-water bath, be warming up to 40~60 DEG C reaction 20~
40 minutes, then temperature rising reflux；It is 1 that volume ratio is added after reaction:1 water and ethyl acetate makes solid be precipitated, filters, is dry
It is dry to obtain compound 6, the high nitre phenyl intermediates of purity can be obtained in this way, for follow-up high-purity and high yield depression medicine
The preparation of object impurity isomers.
In step (a), be added the compound 2 DMF solution reacted after, filtered, filter cake is beaten with toluene
Washing is multiple, and to be layered, water phase toluene extracts at least once merging filtrate, merges organic phase and washing is multiple, then with full
It is spin-dried for drying after brine It, column chromatography purifies to obtain the compound 3, can further increase the pure of compound 3 in this way
Degree.In step (b), merge organic phase after layering extraction, the sodium bicarbonate solution for being 5% with mass fraction washs, and is revolved after dry
It is dry, it carries out column chromatography for separation and obtains the compound 4, to further increase the purity of compound 4.Step (a) and step (b) regardless of
Successively..
It is described in detail below in conjunction with to the preferred embodiment of the invention：
Embodiment 1
The present embodiment provides a kind of preparation method of antidepressant agents impurity isomers chlorine nitre phenyl intermediates and it is based on
The preparation method of its antidepressant agents impurity isomers, as shown in Figure 1, it includes the following steps：
(a) 50g 2- nitro -4- chlorotoluenes, 120mL DMF (i.e. N, N- dimethyl are sequentially added in 500mL there-necked flasks
Formamide) and 55.6g n,N-Dimethylformamide dimethylacetal (DMFDMA), it is stirred clear mixed to obtain dissolving
Close liquid (stirring dissolved clarification, similarly hereinafter)；Outer temperature (being heated with oil bath, outer temperature refers to the temperature of oil bath or other baths, similarly hereinafter) rises
To 150 DEG C of progress back flow reaction 32h, stops heating, obtain the crude product containing compound 2；
178g sodium metaperiodates, 580mL water, 288mL DMF are added in 2L there-necked flasks, 233g is direct plungeed into after stirring evenly
Crude product above-mentioned, normal-temperature reaction 4h is with the reaction was complete；It filtering, filter cake 200ml toluene is beaten washing 3 times, and merging filtrate is layered,
Water phase 100mL toluene extracts primary；Merge organic phase, be washed with water 3 times, saturated common salt wash 1 time after drying be spin-dried for, column chromatography
Purifying obtains 22g compounds 3；Nuclear-magnetism resolves to：1H NMR(400MHz,CDCl3)δ(ppm):10.40(s,1H),8.12(d,J
=2.0Hz, 1H), 7.96 (d, J=4.0Hz, 1H), 7.78 (d, J=4.0Hz, 1H), i.e., as shown in Figure 2.
(b) 50g compounds 3,50g NBS (i.e. N-bromosuccinimide), 0.3g BPO are added in 500mL there-necked flasks
(i.e. dibenzoyl peroxide) and 300mL carbon tetrachloride, outer temperature rise to 90 DEG C, and reaction is for 24 hours (at this point, TLC shows that the reaction was complete)；
Reaction solution is poured into 500mL ice water, adjusts pH to 10 with 2N (equivalent concentration) sodium hydroxide solution, layering extraction merges
Organic phase is washed once with 5% sodium bicarbonate (mass concentration, similarly hereinafter) solution, is spin-dried for after dry, column chromatography for separation obtains 52gization
Closing object 4 (yield 75%), (nuclear magnetic spectrum of compound 4 is as shown in figure 3, specifically resolve to：1H NMR(400MHz,CDCl3)δ
(ppm):7.58 (d, J=2.0Hz, 1H), 7.38 (d, J=4.0Hz, 1H), 7.28 (d, J=4.0Hz, 1H), 4.55 (s,
1H))；
50g compounds 4 and 55mL triethyl phosphites are added in 10mL single port bottles, 150 are risen to after reacting 1h at 120 DEG C
DEG C reaction 2h (at this time TLC show raw material disappear), uses column chromatography after concentration, obtains 5 (yield of 55.3g compounds：91%)；
(nuclear magnetic spectrum of compound 5 is as shown in figure 4, specifically resolve to：1H NMR(400MHz,CDCl3)δ(ppm):7.56(br,1H),
7.37 (dd, J=4.0Hz, 1H), 7.24 (dd, J=4.0Hz, 1H), 4.04 (q, J=8.0Hz, 4H), 3.33 (d, J=
8.0Hz, 2H), 1.25 (t, J=8.0Hz, 6H))；
(c) 10g compounds 3,21.6g compounds 5 and 100mL DME (i.e. glycol dinitrates are added in 250mL there-necked flasks
Ether), dissolved clarification is stirred, the sodium hydrogen (i.e. the DMF solution of sodium hydride, content 60wt%) of 2.3g is added under conditions of ice-water bath, adds
Complete to rise to 50 DEG C of reaction 0.5h, heating carries out back flow reaction 2h, is cooled to 50 DEG C the reaction was continued that (TLC was shown instead at this time in 10 hours
It should be complete；Water (50mL) and ethyl acetate (50mL) is added, a large amount of solids are precipitated, and filter, and filter cake is taken out after being beaten 30min with ethyl alcohol
Filter, is dried to obtain the compound 6 (yield 43%) of 8.5g；(nuclear magnetic spectrum of compound 6 is as shown in figure 5, specifically resolve to：1H NMR(400MHz,CDCl3)δ(ppm):8.01 (br, 1H), 7.74 (d, J=4.0Hz, 1H), 7.63-7.61 (m, 3H),
7.47 (d, J=8.0Hz, 1H), 7.37-7.32 (m, 2H)).
(d) be added in 500mL there-necked flasks 8g compounds 6,1.85g rhodiums Pd/carbon catalyst, 0.4g morpholines, 60mL methanol and
180mL ethyl alcohol directly filters in a hydrogen atmosphere in room temperature reaction 40h, and filtrate is spin-dried for obtaining the 7 (yield of compound of 7.59g
94%)；
(e) 7.59g compounds 7,45mL formic acid and 3.0g sodium formates, outer temperature are added in 100mL single port bottles and rise to 110 DEG C
Back flow reaction 2.5h (the reaction was complete for the raw material of TLC displays at this time), natural cooling, a large amount of solids are precipitated, and 50mL water, stirring is added
30min；It pours the mixture into again in 100mL water, stirs 30min, filter, filter cake twice, is dried to obtain with a small amount of water wash
6.5g compounds 8 (yield 79%)；
(f) compound 8 (6.5g, 17.55mmol, 1.0eq.) is dissolved in DMSO (2ml) in there-necked flask, be added anhydrous
K2CO3(2.89g, 21.06mmol, 1.2eq.), Cu powder (680mg, 10.34mmol, 0.59eq.) and CuBr (845mg,
5.80mmol, 0.33eq.), reaction 3h (160 DEG C of oil temperature), obtains intermediate state compound 9 under nitrogen protection；Stop heating, waits for cold
But to 50 DEG C, 5N NaOH solutions are added, then are warming up to 75 DEG C of reaction 1h, reaction solution are poured into water, with EA (i.e. ethyl acetate)
Extraction, filtering, filtrate use 1N HCl solutions, 10wt%NaHCO respectively3Solution washs, anhydrous sodium sulfate drying；It is concentrated after filtering
Crude product is obtained, is beaten with PE/DCM (i.e. petroleum ether/dichloromethane) mixed solvent, obtains compound 10 (3.0g, yield 65%)；
(nuclear magnetic spectrum of compound 10 is as shown in fig. 6, specifically resolve to：1H NMR(400MHz,CDCl3)δ(ppm):6.95 (d, J=
4.0Hz,2H),7.77-7.73(m,4H),5.95(br,1H),3.00(s,4H))。
(g) compound 10 (3g, 11.4mmol, 1eq) and 7mL toluene, stirring and dissolving, nitrogen are added in 100mL there-necked flasks
Gas is replaced, and sodium hydride (1.13g, 28.2mmol, 2.5eq) is added, is warming up to 100 DEG C of reactions, is cooled to 70 DEG C and 3- (N, N- is added dropwise
Dimethyl) amino-n-propyl chloride hydrochloride (1.52g, 12.6mmol, 1.1eq, CAS:5407-04-5), it adds and is warming up to 100
DEG C reaction to TLC monitoring the reaction was complete；Reaction cooling, pours into ice water, ethyl acetate is added to be layered, and water phase is extracted to no product,
Merge organic phase saturated common salt water washing, drying is spin-dried for, and petroleum ether and stirring is added to be beaten to obtain (the i.e. final production of 2.76g compounds 1
Object, yield 70%, purity 99.6%；The nuclear magnetic spectrum of compound 1 is as shown in fig. 7, specifically resolve to：1H NMR(400MHz,
CDCl3)δ(ppm):7.05-7.00 (m, 4H), 6.91 (d, J=4.0Hz, 2H), 3.71 (t, J=8.0Hz, 2H), 3.09 (s,
4H), 3.33 (t, J=8.0Hz, 2H), 2.17 (s, 4H), 1.74-1.71 (m, 2H) .ESI-MS m/z calcd:C19H22Cl2N2
([M+H]+)；348.12,found:348.2；The purity of aforementioned each reaction product can obtain 99% or more).
Embodiment 2
The present embodiment provides a kind of preparation method of antidepressant agents impurity isomers chlorine nitre phenyl intermediates and it is based on
The preparation method of its antidepressant agents impurity isomers, it with it is almost the same in embodiment 1, unlike：In step (c)
3.0g sodium hydrogen is added, finally obtains 11.5g compounds 6 (yield 59%, purity 99.5%).
Embodiment 3
The present embodiment provides a kind of preparation method of antidepressant agents impurity isomers chlorine nitre phenyl intermediates and it is based on
The preparation method of its antidepressant agents impurity isomers, it with it is almost the same in embodiment 1, unlike：In step (f)
2.56g anhydrous Ks are added2CO3, finally obtain 2.9g compounds 10 (yield 63%, purity 99.0%).
Embodiment 4
The present embodiment provides a kind of preparation method of antidepressant agents impurity isomers, it and basic one in embodiment 1
It causes, unlike, in step (f), filtrate does not carry out following operate：HCl solution, NaHCO are used respectively3Solution washs, anhydrous sulphur
Sour sodium drying, crude product is concentrated to give after filtering；PE/DCM mixed solvents are used to be beaten again；Finally obtain 10 (yield of 2.5g compounds
For 60%, purity 99%).
Embodiment 5
The present embodiment provides a kind of preparation method of antidepressant agents impurity isomers chlorine nitre phenyl intermediates and it is based on
The preparation method of its antidepressant agents impurity isomers, it with it is almost the same in embodiment 1, unlike：Step (g)
In, 3- (N, N- dimethyl) amino-n-propyl chloride hydrochloride is added dropwise at a temperature of 90~110 DEG C, rather than be cooled to 60~80 DEG C；
The yield 68% of final product, purity 99.0%.
Comparative example 1
This example provides a kind of preparation method of antidepressant agents impurity isomers, it with it is almost the same in embodiment 1, no
Be：In step (f), it is not added into anhydrous K2CO3(2.89g, 21.06mmol, 1.2eq.), Cu powder (680mg,
10.34mmol, 0.59eq.) and CuBr (845mg, 5.80mmol, 0.33eq.), do not obtain compound 1 finally.
The above embodiments merely illustrate the technical concept and features of the present invention, and its object is to allow person skilled in the art
Scholar cans understand the content of the present invention and implement it accordingly, and it is not intended to limit the scope of the present invention, all according to the present invention
Equivalent change or modification made by Spirit Essence, should be covered by the protection scope of the present invention.
Claims (4)
1. a kind of preparation method of antidepressant agents impurity isomers chlorine nitre phenyl intermediates, which is characterized in that it includes following
Step：
（a）2- nitro -4- chlorotoluenes, N,N-dimethylformamide and N,N-dimethylformamide dimethylacetal are mixed
It closes, stirs and rise to the DMF solution that 120 ~ 170 DEG C of progress back flow reactions obtain compound 2；Sodium metaperiodate, water and DMF are mixed
It closes, the DMF solution that the compound 2 is then added is reacted, and filtrate is taken to purify to obtain compound 3 after reaction；
（b）The bromo- 4- chlorotoluenes of 2-, N-bromosuccinimide, dibenzoyl peroxide and carbon tetrachloride are mixed, stirred
And it rises to 80 ~ 100 DEG C and is reacted；It is then poured into ice water, pH is adjusted with lye and is layered extraction, purify to obtain compound 4；Again
The compound 4 and triethyl phosphite are mixed, column chromatography for separation obtains compound 5 after being reacted at 120 ~ 150 DEG C；
（c）The compound 3 and the compound 5 are added in glycol dimethyl ether, hydrogenation is added under conditions of ice-water bath
Sodium is warming up to 40 ~ 60 DEG C and reacts 20 ~ 40 minutes, then temperature rising reflux；It is 1 that volume ratio is added after reaction:1 water and acetic acid
Ethyl ester makes solid be precipitated, filters, dry compound 6.
2. the preparation method of antidepressant agents impurity isomers chlorine nitre phenyl intermediates, feature exist according to claim 1
In：Step（a）In, be added the compound 2 DMF solution reacted after, filtered, filter cake with toluene be beaten washing it is more
Secondary, to be layered, water phase toluene extracts at least once merging filtrate, merges organic phase and washes repeatedly, then uses saturated common salt
Drying is spin-dried for after water washing, and column chromatography purifies to obtain the compound 3.
3. the preparation method of antidepressant agents impurity isomers chlorine nitre phenyl intermediates, feature exist according to claim 1
In：Step（b）In, merge organic phase after layering extraction, the sodium bicarbonate solution for being 5% with mass fraction washs, and is revolved after dry
It is dry, it carries out column chromatography for separation and obtains the compound 4.
4. the preparation method of antidepressant agents impurity isomers chlorine nitre phenyl intermediates, feature exist according to claim 1
In：Step（a）And step（b）In no particular order.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114085173A (en) * | 2021-10-18 | 2022-02-25 | 嘉兴学院 | Preparation method of 2-nitro-4-methylsulfonyl benzaldehyde |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114085173A (en) * | 2021-10-18 | 2022-02-25 | 嘉兴学院 | Preparation method of 2-nitro-4-methylsulfonyl benzaldehyde |
| CN114085173B (en) * | 2021-10-18 | 2024-04-16 | 嘉兴学院 | Preparation method of 2-nitro-4-methylsulfonyl benzaldehyde |
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