CN103833636A - Synthetic method of mozavaptan intermediate - Google Patents
Synthetic method of mozavaptan intermediate Download PDFInfo
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- CN103833636A CN103833636A CN201410125311.0A CN201410125311A CN103833636A CN 103833636 A CN103833636 A CN 103833636A CN 201410125311 A CN201410125311 A CN 201410125311A CN 103833636 A CN103833636 A CN 103833636A
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- ketone
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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
- C07D223/16—Benzazepines; Hydrogenated benzazepines
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
The invention relates to a synthetic method of a compound, and in particular a preparation method of 2,3,4,5-tetrahydro-1H-1-benzoazepine-5-acetone. The compound can be applied as an intermediate for preparing vasopressin V2 receptor antagonist mozavaptan. According to the invention, N-vinyl pyrrolidone is taken as a material and rearranged with illumination, then, nitrogen is protected by para-toluene sulfonyl and reacted with 2-butenoic aldehyde to generate nitrogen-protected 2,3,4,5,9,10-hexahydro-1H-1-benzoazepine-5-acetone, aromatized by removing hydrogen in the presence of manganese dioxide, and finally a protecting group is removed to obtain the 2,3,4,5-tetrahydro-1H-1-benzoazepine-5-acetone. Kleiman condensation or Friedle-Crafts reaction in a regular synthetic method is not provided, potassium tert-butanol and aluminum trichloride are avoided, reaction conditions are gentle, materials are easily available, and cost is reduced, and therefore, the synthetic method is more suitable for industrial production.
Description
Technical field
The invention belongs to the synthetic field of medicine, be specifically related to the intermediate 2,3,4 of mozavaptan, the preparation method of 5-tetrahydro-1 H-1-benzazepino-5-ketone.
Background technology
Mozavaptan is a kind of novel vascular vasopressin V 2 Receptor Antagonists, is developed by Japanese Otsuka Pharmaceutical Co., Ltd., in Japan's listing, is used for the treatment of the hyponatremia that heart failure causes in 2006.This medical instrument has urine water Excretion, and Na ion concentration can be provided, and produces useful hemodynamics variation.Convenient oral, does not have medicine tachysnthsis, the significantly untoward reaction such as hypernatremia.Chemistry is by name: 5-(dimethylamino)-1-{4-[(2-methyl benzoyl) amino] benzoyl }-2,3,4,5-tetrahydrochysene-1H-benzazepine, molecular formula is as follows:
The synthetic of mozavaptan cooked very comprehensively summary (Chinese pharmaceutical chemistry magazine 2011,21(2), 130-133 by document), typical method is synthetic according to reaction scheme below:
Gidon Kremer condensation in this synthetic method or Friedle-Crafts reaction, adopt butyl alcohol-tert potassium and aluminum chloride, and single step yield is lower than 70%.
The preparation of butyl alcohol-tert potassium and Gidon Kremer condensation reaction need absolute water-less environment, processing condition harshness, and Friedle-Crafts reaction is anhydrous except requiring in reaction process, emits a large amount of hydrogenchloride in last handling process, and environment is caused damage.
Summary of the invention
Object of the present invention is exactly main intermediate N-p-toluenesulfonyl-2 for mozavaptan, and the synthetic of 3,4,5-tetrahydro-1 H-1-benzazepino-5-ketone (I) provides a kind of raw material to be easy to get, and the three wastes are few, and cost is low, the preparation method of reaction conditions gentleness.Present method is not shown in open source literature report.
Preparation method of the present invention is as follows:
N-p-toluenesulfonyl-2 of the present invention to mozavaptan, 3, 4, the structure of 5-tetrahydro-1 H-1-benzazepino-5-ketone has adopted a kind of new method, the first step reaction reference method (DE2013761) is take NVP as raw material, by the mode of re-irradiation, under illumination, reset to obtain 4-azepine ketone, then after nitrogen being protected with p-methyl benzene sulfonic chloride, under the existence of diaryl D-prolinol derivative, carry out Diels-Alder reaction with crotonic aldehyde and increase a six membered ring, gained six membered ring diene obtains N-p-toluenesulfonyl-2 with Manganse Dioxide oxydehydrogenation method aromatize, 3, 4, 5-tetrahydro-1 H-1-benzazepino-5-ketone, synthesis route is as follows:
Above-mentioned technique the first step reaction NVP (II) is in methyl alcohol, and in 40 ℃, by the low-pressure mercury UV illumination of 50 watts 45 hours, after concentrating under reduced pressure, in acetonitrile, recrystallization obtained 4-azepine ketone (III), yield 80%.
The sulfonylation of above-mentioned technique second step 4-azepine ketone carries out in methylene dichloride, and pyridine, as alkali, reacts 8 hours, obtains N-tolysulfonyl-4-azepine ketone (IV), yield 96%
Above-mentioned technique the 3rd step N-p-toluenesulfonyl-4-azepine ketone carries out Diels-Alder reaction with crotonic aldehyde: this reacts 48 hours, generates N-tolysulfonyl-2,3,4,5,9,10-, six hydrogen-1H-1-benzazepine-5-ketone (V).Yield 71%.
Above-mentioned technique the 4th step N-p-toluenesulfonyl-2,3,4,5; the oxidative dehydrogenation of 10,11-, six hydrogen-1H-1-benzazepine-5-ketone: this reaction 14 hours, pass through heating reflux reaction, obtain N-tolysulfonyl-2; 3,4,5-tetrahydro-1 H-1-benzazepino-5-ketone (VI)
This reaction yield 92%.
Above-mentioned technique the 5th step N-tolysulfonyl-2, the protective reaction of 3,4,5-tetrahydro-1 H-1-benzazepino-5-ketone: this reaction adopts polyphosphoric acid to go protecting group; react 3 hours, obtain 2,3; 4,5-tetrahydro-1 H-1-benzazepino-5-ketone (I), yield 95%.
Above-mentioned technique total recovery has reached 47%.
The innovative point of this reaction is: first reset and built seven Yuans nitrogen heterocyclics by N-vinylpyridine oxazolone; then introduce six membered ring, existing seven Yuans rings are built to diekmann reaction used, pay-Ke acylation reaction replaces with rearrangement reaction; not only reduce reactions steps, and reaction conditions gentleness.
Diels-Alder reaction catalyzer can be any primary amine, and we use (S)-phenylbenzene front three silica crassitude here, and structure is as follows:
Document (Angew.Chem.Int.Ed.2008,47,4719 – 4721) method is pressed in its preparation.
Embodiment:
The following example is for further narration the present invention, but it is not any restriction to scope of the present invention.The purity testing of each compound is measured on HP1100 high performance liquid chromatograph.
Synthesizing of embodiment 1 compound 4-azepine ketone
NVP (30g, 0.27mol) in 1600mL methyl alcohol in 40 ℃ by the low-pressure mercury UV illumination of 50 watts 45 hours, after concentrating under reduced pressure, in acetonitrile, recrystallization obtains 4-azepine ketone 24g, yield 80%.Fusing point: 74-76 ℃.
1H?NMR(400MHz,CDCl
3):δ6.90(d,J=10.9Hz,1H),5.14(d,J=10.9Hz,1H),2.99-2.90(m,4H),2.00(s,1H),1.96-1.86(m,2H)。
The preparation of embodiment 2N-tolysulfonyl-4-azepine ketone
In 500mL single necked round bottom flask, add 4-azepine ketone 24g(0.216mol), methylene dichloride 125ml, pyridine 125ml, and 4-dimethylamino pyridine 0.3g, then add Tosyl chloride 41.18g(0.216mol), this mixed solution stirs 8 hours at ambient temperature.Then add 100mL1N hydrochloric acid, dichloromethane extraction (50mL × 3), merges organic phase, uses anhydrous Na
2sO
4dry, after filtering, filtrate decompression is concentrated, obtains white solid 55.0g (0.207mol), yield 96%.
1H?NMR(400MHz,CDCl
3):δ7.74(dd,J=7.5,1.5Hz,2H),7.40(dd,J=7.5,1.5Hz,2H),6.92(d,J=10.9Hz,1H),5.14(d,J=10.9Hz,1H),3.16(m,2H),2.94(m,2H),2.34(s,3H),1.96-1.86(m,2H)。
Embodiment 3N-p-toluenesulfonyl-2, the preparation of 3,4,5,10,11-, six hydrogen-1H-1-benzazepine-5-ketone
In 50mL round bottom single port flask, add N-p-toluenesulfonyl-4-azepine ketone (2.65g; 10mmol); crotonic aldehyde (700mg; 1.0mmol); (S)-phenylbenzene front three silica crassitude (50mg), chloroform (15ml), p-nitrobenzoic acid (50mg); room temperature reaction uses column chromatography to obtain product 2.25g(7.1mmol after 48 hours), yield 71%.
1H?NMR(400MHz,CDCl
3):δ7.74(dd,J=7.5,1.5Hz,2H),7.40(dd,J=7.5,1.5Hz,2H),6.81(dd,J=6.2,1.0Hz,1H),5.90-5.80(m,2H),3.30-2.92(m,5H),2.40-2.33(m,2H),2.33(s,3H),1.97-1.86(m,2H)。
Embodiment 4N-tolysulfonyl-2, the preparation of 3,4,5-tetrahydro-1 H-1-benzazepino-5-ketone
N-p-toluenesulfonyl-2; 3,4,5; 10; 11-six hydrogen-1H-1-benzazepine-5-ketone (476mg, 1.5mmol), Manganse Dioxide (1.5g) and toluene (10ml) reflux 20 hours in single port flask; after cooling; concentrating under reduced pressure, it is white solid powder 435mg(1.38mmol that enriched material obtains principal product through column chromatography for separation), yield 92%.
1H?NMR(400MHz,CDCl3):δ7.71-7.69(m,1H),7.53-7.46(m,1H),7.41-7.38(m,4H),6.85-6.68(m,2H),3.87-3.84(m,2H),2.59-2.55(m,2H),2.42-2.38(m,3H),1.97-1.93(m,2H)。
Embodiment 52,3,4, the preparation of 5-tetrahydro-1 H-1-benzazepino-5-ketone
After being preheating to 80-100 ℃, 3g polyphosphoric acid adds N-tolysulfonyl-2,3,4,5-tetrahydro-1 H-1-benzazepino-5-ketone (315mg, 1.0mmol), then maintain 90-100 ℃ and stir 3 hours, reaction solution is poured in frozen water, be neutralized to pH8-9 with aqueous sodium hydroxide solution, with dichloromethane extraction, dried over mgso, suction filtration, concentrated, concentrated solution is through column chromatography purification, with sherwood oil: ethyl acetate (3:1) wash-out, after concentrated, obtain faint yellow solid 153mg, (0.95mmol), yield 95%.
1H?NMR(400MHz,CDCl3):δ7.71-7.69(m,1H),7.53-7.46(m,1H),6.75-6.61(m,2H),5.58-5.54(t,1H),3.87-3.84(m,2H),2.59-2.55(m,2H),1.97-1.93(m,2H)。
Claims (6)
1. one kind as the mozavaptan intermediate 2 of structural formula I; 3; 4,5-tetrahydro-1 H-1-benzazepino-5-ketone preparation method, is characterized in that: by N-tolysulfonyl-2; 3; 4,5-tetrahydro-1 H-1-benzazepino-5-ketone (VI) strong acid exist down protect 2,3; 4,5-tetrahydro-1 H-1-benzazepino-5-ketone
2. preparation method according to claim 1, is characterized in that: strong acid is polyphosphoric acid.
3. preparation method according to claim 1, it is characterized in that: N-tolysulfonyl-2,3,4,5,9,10-six hydrogen-1H-1-benzazepine-5-ketone (V) aromatize under Manganse Dioxide exists obtains N-tolysulfonyl-2,3,4,5-tetrahydro-1 H-1-benzazepino-5-ketone (VI).
4. preparation method according to claim 3, it is characterized in that: N-tolysulfonyl-4-azepine ketone (IV) reacts with crotonic aldehyde and generates N-tolysulfonyl-2 under the existence of diaryl D-prolinol derivative, 3,4,5,9,10-, six hydrogen-1H-1-benzazepine-5-ketone (V).
5. preparation method according to claim 4, is characterized in that: diaryl D-prolinol derivative is (S)-phenylbenzene front three silica crassitude.
6. preparation method according to claim 4; it is characterized in that: NVP (II) is raw material; under illumination, reset to obtain 4-azepine ketone (III), obtain N-tolysulfonyl-4-azepine ketone (IV) by Tosyl chloride acidylate.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1863778A (en) * | 2003-10-08 | 2006-11-15 | 伊莱利利公司 | Compounds and methods for treating dyslipidemia |
| CN102702103A (en) * | 2012-05-17 | 2012-10-03 | 盛世泰科生物医药技术(苏州)有限公司 | Preparation method of 2,3,4,5-tetrahydro-1H-benzo[b]azepine |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1863778A (en) * | 2003-10-08 | 2006-11-15 | 伊莱利利公司 | Compounds and methods for treating dyslipidemia |
| CN102702103A (en) * | 2012-05-17 | 2012-10-03 | 盛世泰科生物医药技术(苏州)有限公司 | Preparation method of 2,3,4,5-tetrahydro-1H-benzo[b]azepine |
Non-Patent Citations (1)
| Title |
|---|
| PATRICIA GARCIA－GARCIA等: "Catalytic asymmetric michael reactions of acetaldehyde", 《ANGEWANDTE CHEMIE》, vol. 47, no. 25, 28 April 2008 (2008-04-28), pages 4719 - 4721 * |
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