CN103833636B - A kind of synthetic method of mozavaptan intermediate - Google Patents
A kind of synthetic method of mozavaptan intermediate Download PDFInfo
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- CN103833636B CN103833636B CN201410125311.0A CN201410125311A CN103833636B CN 103833636 B CN103833636 B CN 103833636B CN 201410125311 A CN201410125311 A CN 201410125311A CN 103833636 B CN103833636 B CN 103833636B
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- ketone
- benzazepino
- tetrahydro
- tolysulfonyl
- mozavaptan
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- 0 CCCCNC(C(C)*)[C@](C)c1ccccc1 Chemical compound CCCCNC(C(C)*)[C@](C)c1ccccc1 0.000 description 2
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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
Abstract
The present invention relates to a kind of synthetic method of compound, specifically the preparation method of 2,3,4,5-tetrahydro-1 H-1-benzazepino-5-ketones; This compound can as the intermediate preparing vasopressing V2 receptor antagonist mozavaptan (Mozavaptan).The method take NVP as raw material, reset under light illumination, then nitrogen p-toluenesulfonyl is protected, then generate that nitrogen protects 2 are reacted with crotonic aldehyde, 3, 4, 5, 9, 10-six hydrogen-1H-1-benzazepine-5-ketone, dehydrogenation aromatize under Manganse Dioxide exists, blocking group is finally gone to obtain 2, 3, 4, 5-tetrahydro-1 H-1-benzazepino-5-ketone, owing to reacting without the Gidon Kremer condensation in conventional synthesis process or Friedle-Crafts, avoid butyl alcohol-tert potassium and aluminum chloride, reaction conditions is gentle, raw material is easy to get, cost reduces, suitability for industrialized production preferably.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, be specifically related to the preparation method of intermediate 2,3,4, the 5-tetrahydro-1 H-1-benzazepino-5-ketone of mozavaptan.
Background technology
Mozavaptan is a kind of novel vascular vasopressin V 2 Receptor Antagonists, is developed by Japanese Otsuka Pharmaceutical Co., Ltd., in 2006 in Japan's listing, is used for the treatment of the hyponatremia that heart failure causes.This medical instrument has urine water Excretion, can provide Na ion concentration, produce 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) is amino] benzoyl }-2,3,4,5-tetrahydrochysene-1H-benzazepines, molecular formula is as follows:
The synthesis of mozavaptan has been done by document and has very comprehensively been summarized (Chinese pharmaceutical chemistry magazine 2011,21(2), 130-133), typical method is according to reaction scheme synthesis below:
Gidon Kremer condensation in this synthetic method or Friedle-Crafts reaction, adopt butyl alcohol-tert potassium and aluminum chloride, single step yield is lower than 70%.
Preparation and the Gidon Kremer condensation reaction of butyl alcohol-tert potassium need absolute environment, and processing condition are harsh, and Friedle-Crafts reaction is anhydrous except requiring in reaction process, releases a large amount of hydrogenchloride, to environmental concerns in last handling process.
Summary of the invention
Object of the present invention is exactly that the three wastes are few, and cost is low, the preparation method of reaction conditions gentleness for the synthesis of the main intermediate N-p-toluenesulfonyl-2,3,4,5-tetrahydro-1 H-1-benzazepino-5-ketone (I) of mozavaptan provides a kind of raw material to be easy to get.Present method is not shown in that open source literature is reported.
Preparation method of the present invention is as follows:
The present invention is to the N-p-toluenesulfonyl-2 of mozavaptan, 3, 4, the structure of 5-tetrahydro-1 H-1-benzazepino-5-ketone have employed a kind of new method, the first step reaction reference method (DE2013761) take NVP as raw material, by the mode of re-irradiation, reset to obtain 4-azepine ketone under light illumination, then under the existence of diaryl D-prolinol derivative, carry out Diels-Alder reaction after nitrogen being protected with p-methyl benzene sulfonic chloride with crotonic aldehyde increase a six membered ring, gained six membered ring diene manganese dioxide dehydriding aromatize obtains N-p-toluenesulfonyl-2, 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 DEG C of low-pressure mercury UV illumination 45 hours with 50 watts, after concentrating under reduced pressure, in acetonitrile, recrystallization obtains 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 and crotonic aldehyde carry out Diels-Alder reaction: this reaction 48 hours, generate 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, through heating reflux reaction, will obtain N-tolysulfonyl-2; 3,4,5-tetrahydro-1 H-1-benzazepino-5-ketone (VI)
This reaction yield 92%.
The protective reaction of above-mentioned technique the 5th step N-tolysulfonyl-2,3,4,5-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 process overall yields reaches 47%.
The innovative point of this reaction is: first reset structure seven Yuans nitrogen heterocyclics by N-vinylpyridine oxazolone; then introduce six membered ring, existing seven Yuans rings are built diekmann reaction used, Fu Zhongsun rearrangement reaction replaces; not only reduce reactions steps, and reaction conditions is gentle.
Diels-Alder reaction catalyzer can be any primary amine, we here use (S)-phenylbenzene front three silica crassitude, 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 used for describing the present invention further, but it is not any restriction to scope of the present invention.The purity testing of each compound measures on HP1100 high performance liquid chromatograph.
The synthesis of embodiment 1 compound 4-azepine ketone
NVP (30g, 0.27mol) is in 40 DEG C of low-pressure mercury UV illumination 45 hours with 50 watts in 1600mL methyl alcohol, and after concentrating under reduced pressure, in acetonitrile, recrystallization obtains 4-azepine ketone 24g, yield 80%.Fusing point: 74-76 DEG C.
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
4-azepine ketone 24g(0.216mol is added) in 500mL single necked round bottom flask, methylene dichloride 125ml, pyridine 125ml, and 4-dimethylamino pyridine 0.3g, then Tosyl chloride 41.18g(0.216mol is added), this mixed solution stirs 8 hours at ambient temperature.Then add 100mL1N hydrochloric acid, dichloromethane extraction (50mL × 3), merge organic phase, use anhydrous Na
2sO
4drying, filtrate reduced in volume after filtering, 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)。
The preparation of embodiment 3N-p-toluenesulfonyl-2,3,4,5,10,11-six hydrogen-1H-1-benzazepine-5-ketone
N-p-toluenesulfonyl-4-azepine ketone (2.65g is added in 50mL round bottom single port flask; 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)。
The preparation of embodiment 4N-tolysulfonyl-2,3,4,5-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)。
The preparation of embodiment 52,3,4,5-tetrahydro-1 H-1-benzazepino-5-ketone
N-tolysulfonyl-2 is added after 3g polyphosphoric acid is preheating to 80-100 DEG C, 3,4,5-tetrahydro-1 H-1-benzazepino-5-ketone (315mg, 1.0mmol), then maintain 90-100 DEG C to 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, faint yellow solid 153mg is obtained, (0.95mmol), yield 95% after concentrated.
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 (2)
1. the mozavaptan intermediate 2,3,4 as structural formula I, 5-tetrahydro-1 H-1-benzazepino-5-ketone preparation method, 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); Go down to protect to obtain 2,3,4,5-tetrahydro-1 H-1-benzazepino-5-ketones by N-tolysulfonyl-2,3,4,5-tetrahydro-1 H-1-benzazepino-5-ketone (VI) in polyphosphoric acid existence
2. preparation method according to claim 1, it is characterized in that: NVP (II) is raw material, reset to obtain 4-azepine ketone (III) under light illumination, obtain N-tolysulfonyl-4-azepine ketone (IV) by Tosyl chloride acidylate; N-tolysulfonyl-4-azepine ketone (IV) reacts with crotonic aldehyde and generates N-tolysulfonyl-2,3,4,5,9,10-six hydrogen-1H-1-benzazepine-5-ketone (V) under the existence of diaryl D-prolinol derivative; Described diaryl D-prolinol derivative is (S)-phenylbenzene front three silica crassitude, and structure is as follows:
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