CN107286093A - The preparation method of 6 chloromethyl morphanthridines - Google Patents
The preparation method of 6 chloromethyl morphanthridines Download PDFInfo
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- CN107286093A CN107286093A CN201710705230.1A CN201710705230A CN107286093A CN 107286093 A CN107286093 A CN 107286093A CN 201710705230 A CN201710705230 A CN 201710705230A CN 107286093 A CN107286093 A CN 107286093A
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- morphanthridine
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- C—CHEMISTRY; METALLURGY
- 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
- C07D223/20—Dibenz [b, e] azepines; Hydrogenated dibenz [b, e] azepines
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
- B01J31/226—Sulfur, e.g. thiocarbamates
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/30—Complexes comprising metals of Group III (IIIA or IIIB) as the central metal
- B01J2531/37—Lanthanum
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Abstract
The invention belongs to field of pharmaceutical chemistry technology, and in particular to a kind of preparation method of 6 chloromethyl morphanthridine.Described preparation method is under concentrated sulfuric acid effect, using N [2 (phenyl methyl) phenyl] 2 chloroacetamides as raw material, using the complex compound of trifluoromethanesulfonic acid rare earth compound and dimethyl sulfoxide (DMSO) as catalyst, dehydration condensation prepares 6 chloromethyl morphanthridines.The present invention uses the complex compound of trifluoromethanesulfonic acid rare earth compound and dimethyl sulfoxide (DMSO) to achieve good effect for catalyst, and present invention pollution is small, environmentally friendly, is recycled production.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, and in particular to a kind of preparation method of 6- chloromethyls morphanthridine.
Background technology
6- chloromethyl morphanthridines are antidepressants mianserin hydrochloride and histamine H 1 receptor antagonist epinastine hydrochloride
Important intermediate in building-up process.Mianserin hydrochloride effect is similar to imipramine, with angst resistance effect, seldom causes low
Blood pressure, is particularly suitable for use in old age and with cardiopathic patients with depression, it can also be used to treat primary anxiety disorder or with suppression
The anxiety disorder of strongly fragrant disease.Epinastine hydrochloride has suppression to histamine, leukotriene C, platelet activating factor (PAF), serotonin
Effect, and histamine, the release of slow reacting substance A (SRS-A) chemical mediator can be suppressed, epinastine hydrochloride is difficult to by blood in addition
Brain barrier, the H1 receptor antagonisms of Central nervous system are weak, drowsiness Small side effects.
“Stereoselective synthesis of(R)-(-)-mianserin”J.et al./
Tetrahedron:The synthetic method for the 6- chloromethyl morphanthridines that Asymmetry 14 (2003) 3335-3342 is reported is by N-
[2- (phenyl methyl) phenyl] -2- chloroacetamides are raw material, under POCl3 effect, are occurred than Shi Le-Na Piyelaersi
Base reaction (Bischler-Napieralski-Type) is prepared.React conventional than Shi Le-Na Piyela Bielskis to take off
Water reagent has phosphoric acid class such as：Phosphorus pentachloride, phosphorus pentoxide, POCl3, polyphosphoric acids etc.；Louis's acids is such as：Four chlorinations
Tin, zinc dichloride, titanium tetrachloride etc..Either phosphoric acid class or general Louis's acids, extremely unstable in water, easily divides
Solution, usage amount is big, it is impossible to recycle, and post-processes cumbersome, and waste water and waste liquid amount is big, and environmental pollution is serious.
The content of the invention
It is an object of the invention to provide a kind of preparation method of 6- chloromethyls morphanthridine, small, environmentally friendly, energy is polluted
Enough circulation production.
The preparation method of 6- chloromethyls morphanthridine of the present invention is as follows：
It is dilute with trifluoromethanesulfonic acid as raw material using N- [2- (phenyl methyl) phenyl] -2- chloroacetamides under concentrated sulfuric acid effect
The complex compound of earth compounds and dimethyl sulfoxide (DMSO) is catalyst, and dehydration condensation prepares 6- chloromethyl morphanthridines.
Wherein：
The usage ratio of trifluoromethanesulfonic acid rare earth compound and dimethyl sulfoxide (DMSO) is 0.001-0.005:1, trifluoromethanesulfonic acid
Rare earth compound is in terms of mol, and dimethyl sulfoxide (DMSO) is in terms of ml.
Trifluoromethanesulfonic acid rare earth compound is Ytterbiumtriflate, trifluoromethanesulfonic acid lanthanum or trifluoromethanesulfonic acid scandium.
N- [2- (phenyl methyl) phenyl] -2- chloroacetamides, the concentrated sulfuric acid, the mol ratio of trifluoromethanesulfonic acid rare earth compound are
1:0.1-0.3:0.01-0.05。
The preparation method of 6- chloromethyls morphanthridine of the present invention, specifically includes following steps：
(1) N- [2- (phenyl methyl) phenyl] -2- chloroacetamides are added in toluene, add the concentrated sulfuric acid, catalyst,
Heating, insulation, separation water outlet and part toluene；
(2) solution cooling, the insulation obtained step (1), then suction filtration, drying, obtain 6- chloromethyl morphanthridines.
Wherein：
Toluene, the volume mass ratio of N- [2- (phenyl methyl) phenyl] -2- chloroacetamides are 90-100:13, toluene is with ml
Meter, N- [2- (phenyl methyl) phenyl] -2- chloroacetamides are in terms of g.
In step (1), 90-100 DEG C is warming up to, 2-3h is incubated.
In step (2), 0-10 DEG C is cooled to, 1-2h is incubated.
In step (2), drying temperature is 40-50 DEG C, and drying time is 8-10h.
6- chloromethyl morphanthridines yield is 94%-96%, and purity is 97%-99.5%.
The toluene that the present invention isolates step (1) is mixed with the mother liquor that step (2) suction filtration is obtained, and returning to reaction cycle makes
With.
The course of reaction of the present invention is as follows：
Beneficial effects of the present invention are as follows：
Trifluoromethanesulfonic acid rare earth compound is the new strong lewis acid of a class, compared with traditional lewis acid, they
Advantage be moisture-stable, recyclable recycling, and in most cases, only catalytic amount can complete reaction.
In view of the shortcomings of the prior art, the present invention is under the conditions of the concentrated sulfuric acid, first with trifluoromethanesulfonic acid rare earth compound (Re
(OTf)3) it is catalyst, dehydration condensation obtains 6- chloromethyl morphanthridines.But its yield only has 75%, and mother liquor is
When secondary recovery is applied mechanically, yield is only 40%.In order to improve the efficiency of yield and recovery, present invention employs a variety of trifluoros
The complex compound of methanesulfonic acid rare earth, wherein by taking the complex compound of Ytterbiumtriflate as an example, part is tetrahydrofuran (THF), tricresyl phosphate
Butyl ester (TBP), dimethyl sulfoxide (DMSO) (DMSO), trim,ethylchlorosilane (TMSCl), reaction result such as table 1.From table 1 it follows that
The complex compound of Ytterbiumtriflate has obvious advantage on yield and recovery efficiency than single Ytterbiumtriflate, its
In with Yb (OTf)3DMSO is optimal.The reaction green circulatory is produced, it is to avoid be difficult to receive using polyphosphoric acids, POCl3 etc.
Return, usage amount is very big, with serious pollution reagent.
The reaction result of the different trifluoromethanesulfonic acid ytterbium complexs of table 1
The present invention is using Re (OTf)3Achieve good effect as catalyst with DMSO complex compound, this be probably because
To be not added with during DMSO, activated centre is C-RE σ keys, and this activated centre is not sufficiently stable, easy in inactivation, and is added after DMSO in activity
The heart is changed into allylic structure by C-RE σ keys, and this active sites is relatively stable, not easy in inactivation.In addition, in the present invention first
A part of toluene is steamed, then is cooled, is the raising 6- chloromethanes in order to ensure that 6- chloromethyls morphanthridine is separated out from reaction solution as far as possible
The yield of base morphanthridine.
Embodiment
The present invention is described further with reference to embodiments.
Embodiment 1
26.0g (0.10mol) N- [2- (phenyl methyl) phenyl] -2- chloroacetamides and 200ml toluene are added to 500ml tetra-
Mouth bottle, adds 2.0g (0.02mol) concentrated sulfuric acid, and stirring adds 0.62g (0.001mol) Ytterbiumtriflates and 1ml DMSO,
100 DEG C are warming up to, 2 hours is incubated, goes out moisture in course of reaction.Insulation terminates, and distills out about 75ml toluene, starts to be cooled to
10 DEG C, 1 hour is incubated, suction filtration, 50 DEG C of dry 8h obtain 6- chloromethyl morphanthridine 23g, purity 99.3%, yield 95.1%.
The complete mother liquor of suction filtration and the toluene distilled out are mixed, 26.0gN- [2- (phenyl methyl) phenyl] -2- chlorine is added
Acetamide, is operated as stated above, is applied mechanically a mother liquor and be can obtain 6- chloromethyl morphanthridine 21.9g, purity 98.7%, yield
90.8%.
Its experimentation of the data obtained in table 1 is different except catalyst, and its reactions steps is same as Example 1.
Embodiment 2
26.0g (0.10mol) N- [2- (phenyl methyl) phenyl] -2- chloroacetamides and 180ml toluene are added to 500ml tetra-
Mouth bottle, adds 1.0g (0.01mol) concentrated sulfuric acid, and stirring adds 2.93g (0.005mol) trifluoromethanesulfonic acid lanthanums and 1ml DMSO,
90 DEG C are warming up to, 2.5 hours is incubated, goes out moisture in course of reaction.Insulation terminates, and distills out about 75ml toluene, starts cooling
To 5 DEG C, 2 hours are incubated, suction filtration, 40 DEG C of dry 10h obtain 6- chloromethyl morphanthridine 23.1g, purity 99.1%, yield
95.8%.
The complete mother liquor of suction filtration and the toluene distilled out are mixed, 26.0gN- [2- (phenyl methyl) phenyl] -2- chlorine is added
Acetamide, is operated as stated above, is applied mechanically a mother liquor and be can obtain 6- chloromethyl morphanthridine 22g, purity 98.9%, yield
91%.
Embodiment 3
26.0g (0.10mol) N- [2- (phenyl methyl) phenyl] -2- chloroacetamides and 190ml toluene are added to 500ml tetra-
Mouth bottle, adds 3.0g (0.03mol) concentrated sulfuric acid, and stirring adds 0.98g (0.002mol) trifluoromethanesulfonic acid scandiums and 1ml DMSO,
95 DEG C are warming up to, 3 hours is incubated, goes out moisture in course of reaction.Insulation terminates, and distills out about 75ml toluene, starts to be cooled to 2
DEG C, 1 hour is incubated, suction filtration, 45 DEG C of dry 9h obtain 6- chloromethyl morphanthridine 23g, purity 98.7%, yield 95.3%.
The complete mother liquor of suction filtration and the toluene distilled out are mixed, 26.0gN- [2- (phenyl methyl) phenyl] -2- chlorine is added
Acetamide, is operated as stated above, is applied mechanically a mother liquor and be can obtain 6- chloromethyl morphanthridine 21.8g, purity 98.5%, yield
90.5%.
Comparative example 1
Catalyst in embodiment 1 is changed to 0.001mol Ytterbiumtriflates, other conditions are constant.Obtain 6- chloromethyls
Morphanthridine 18.1g, its yield 75.1%, purity is 97.6%；Apply mechanically a mother liquor and can obtain 6- chloromethyl morphanthridines
9.7g, its yield is 40.3%, and purity is 96.8%.
Comparative example 2
Catalyst in embodiment 1 is changed to 0.001mol Ytterbiumtriflates and 1ml THF, other conditions are constant.
To 6- chloromethyl morphanthridine 20.3g, its yield 84%, purity is 97.8%；Apply mechanically a mother liquor and can obtain 6- chloromethyls
Fen alkane pyridine 15.8g, its yield is 65.5%, and purity is 97.2%.
Comparative example 3
Catalyst in embodiment 1 is changed to 0.001mol Ytterbiumtriflates and 3ml TBP, other conditions are constant.
To 6- chloromethyl morphanthridine 20.8g, its yield 86.3%, purity is 97.5%；Apply mechanically a mother liquor and can obtain 6- chloromethyls
Morphanthridine 18.6g, its yield is 77.2%, and purity is 97.4%.
Comparative example 4
Catalyst in embodiment 1 is changed to 0.001mol Ytterbiumtriflates and 1ml TMSCl, other conditions are constant.
Obtain 6- chloromethyl morphanthridine 21.5g, its yield 89%, purity is 98%；Apply mechanically a mother liquor and can obtain 6- chloromethyls
Fen alkane pyridine 18.8g, its yield is 78%, and purity is 97.7%.
Claims (10)
1. a kind of preparation method of 6- chloromethyls morphanthridine, it is characterised in that：Under concentrated sulfuric acid effect, with N- [2- (phenyl first
Base) phenyl] -2- chloroacetamides be raw material, using the complex compound of trifluoromethanesulfonic acid rare earth compound and dimethyl sulfoxide (DMSO) as catalyst,
Dehydration condensation prepares 6- chloromethyl morphanthridines.
2. the preparation method of 6- chloromethyls morphanthridine according to claim 1, it is characterised in that：Trifluoromethanesulfonic acid rare earth
Compound and the usage ratio of dimethyl sulfoxide (DMSO) are 0.001-0.005:1, trifluoromethanesulfonic acid rare earth compound is in terms of mol, diformazan
Base sulfoxide is in terms of ml.
3. the preparation method of 6- chloromethyls morphanthridine according to claim 1 or 2, it is characterised in that：Trifluoromethanesulfonic acid
Rare earth compound is Ytterbiumtriflate, trifluoromethanesulfonic acid lanthanum or trifluoromethanesulfonic acid scandium.
4. the preparation method of 6- chloromethyls morphanthridine according to claim 1, it is characterised in that：N- [2- (phenyl first
Base) phenyl] -2- chloroacetamides, the concentrated sulfuric acid, trifluoromethanesulfonic acid rare earth compound mol ratio be 1:0.1-0.3:0.01-0.05.
5. the preparation method of 6- chloromethyls morphanthridine according to claim 1, it is characterised in that comprise the following steps：
(1) N- [2- (phenyl methyl) phenyl] -2- chloroacetamides are added in toluene, add the concentrated sulfuric acid, catalyst, risen
Temperature, insulation, separation water outlet and part toluene；
(2) solution cooling, the insulation obtained step (1), then suction filtration, drying, obtain 6- chloromethyl morphanthridines.
6. the preparation method of 6- chloromethyls morphanthridine according to claim 5, it is characterised in that：Toluene, N- [2- (benzene
Ylmethyl) phenyl] -2- chloroacetamides volume mass ratio be 90-100:13, toluene is in terms of ml, N- [2- (phenyl methyl) benzene
Base] -2- chloroacetamides are in terms of g.
7. the preparation method of 6- chloromethyls morphanthridine according to claim 5, it is characterised in that：In step (1), heating
To 90-100 DEG C, 2-3h is incubated.
8. the preparation method of 6- chloromethyls morphanthridine according to claim 5, it is characterised in that：In step (2), cooling
To 0-10 DEG C, 1-2h is incubated.
9. the preparation method of 6- chloromethyls morphanthridine according to claim 5, it is characterised in that：In step (2), dry
Temperature is 40-50 DEG C, and drying time is 8-10h.
10. the preparation method of 6- chloromethyls morphanthridine according to claim 5, it is characterised in that：6- chloromethyl fens
Alkane pyridine yield is 94%-96%, and purity is 97%-99.5%.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109678918A (en) * | 2019-01-24 | 2019-04-26 | 台州仙琚药业有限公司 | The preparation method of 5 α-androstane -2- alkene -17- ketone |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103059053A (en) * | 2013-01-28 | 2013-04-24 | 中国科学院长春应用化学研究所 | Rare earth complex and preparation method thereof, rare earth catalyst system and preparation method of butadiene-isoprene copolymer |
| CN103232410A (en) * | 2013-04-26 | 2013-08-07 | 苏州大学 | Method for preparing 2-amino benzothiazine |
| CN104447757A (en) * | 2014-11-17 | 2015-03-25 | 合肥华方医药科技有限公司 | Method for synthesizing epinastine |
| CN105949455A (en) * | 2016-05-10 | 2016-09-21 | 周荣 | Preparation method of polyethylene glycol hydrogel |
-
2017
- 2017-08-17 CN CN201710705230.1A patent/CN107286093B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103059053A (en) * | 2013-01-28 | 2013-04-24 | 中国科学院长春应用化学研究所 | Rare earth complex and preparation method thereof, rare earth catalyst system and preparation method of butadiene-isoprene copolymer |
| CN103232410A (en) * | 2013-04-26 | 2013-08-07 | 苏州大学 | Method for preparing 2-amino benzothiazine |
| CN104447757A (en) * | 2014-11-17 | 2015-03-25 | 合肥华方医药科技有限公司 | Method for synthesizing epinastine |
| CN105949455A (en) * | 2016-05-10 | 2016-09-21 | 周荣 | Preparation method of polyethylene glycol hydrogel |
Non-Patent Citations (4)
| Title |
|---|
| J. PAWLOWSKA, ET AL.: "Stereoselective synthesis of (R)-(-)-mianserin", 《TETRAHEDRON: ASYMMETRY》 * |
| SHU KOBAYASHI, ET AL.: "Rare-Earth Metal Triflates in Organic Synthesis", 《CHEM. REV.》 * |
| 朱雪华.: "稀土路易斯酸催化碳氮及碳氧键形成研究", 《中国博士学位论文全文数据库·工程科技I辑》 * |
| 李泉，等.: "依匹斯汀中间体6-氯-11H-二苯[b,e]氮杂卓的合成研究", 《应用化工》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109678918A (en) * | 2019-01-24 | 2019-04-26 | 台州仙琚药业有限公司 | The preparation method of 5 α-androstane -2- alkene -17- ketone |
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Address after: 101300 No.9 Mintai Road, Beiwu Town, Shunyi District, Beijing Patentee after: Beijing Jincheng Taier Pharmaceutical Co.,Ltd. Address before: 100020 no.559, Shuangqiao Road, Guanzhuang Township, Chaoyang District, Beijing Patentee before: BEIJING LANEVA PHARMACEUTICAL Co.,Ltd. |