CN103896842B

CN103896842B - A kind of preparation method of tolvaptan intermediate

Info

Publication number: CN103896842B
Application number: CN201410125978.0A
Authority: CN
Inventors: 孙华君; 张军桥; 朱毅; 雷大友; 杨尚金; 谢国范
Original assignee: HUANGGANG FUCHI PHARMACEUTICAL Co Ltd
Current assignee: Hubei Yuanda life science and Technology Co Ltd
Priority date: 2014-03-31
Filing date: 2014-03-31
Publication date: 2015-09-02
Anticipated expiration: 2034-03-31
Also published as: CN103896842A

Abstract

The invention belongs to pharmaceutical synthesis field, be specifically related to the preparation method of chloro-2,3,4,5,10, the 11-six hydrogen-1H-1-benzazepine-5-ketone of tolvaptan intermediate 7-.The method take NVP as raw material, reset to obtain 4-azepine ketone under light illumination, then nitrogen p-toluenesulfonyl is protected, react the 7-chloro-2 generating nitrogen and protect with the chloro-crotonic aldehyde of 2-under the existence of diaryl D-prolinol derivative, 3, 4, 5, 10, 11-six hydrogen-1H-1-benzazepine-5-ketone, dehydrogenation aromatize under Manganse Dioxide exists, blocking group is finally gone to obtain 7-chloro-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

A kind of preparation method of tolvaptan intermediate

Technical field

The invention belongs to pharmaceutical synthesis field, be specifically related to the preparation method of chloro-2,3,4,5,10, the 11-six hydrogen-1H-1-benzazepine-5-ketone of tolvaptan intermediate 7-.

Background technology

Tolvaptan is a kind of specific antagonist arginine vasopressin, is used for the treatment of high capacitive hyponatremia companion heart failure, liver cirrhosis, the syndrome of inapropriate ADH such as perhaps.Chemistry is by name: N-[4-[(5R)-7-chloro-5-hydroxyl-2,3,4,5-tetrahydrochysene-1-benzazepine-1-formyl radical]-3-aminomethyl phenyl]-2-methyl benzamide, and molecular formula is as follows:

The synthesis of tolvaptan has been done by patent documentation and has very comprehensively been summarized (CN102093293A), and typical method is according to reaction scheme synthesis (Drugs of the Future2002,27 (4) below; 350-357):

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 chloro-2,3,4, the 5-tetrahydro-1 H-1-benzazepino-5-ketones (I) of main intermediate 7-of tolvaptan 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 2 of tolvaptan, 3, 4, the structure of 5-tetrahydro-1 H-1-benzazepino-5-ketone have employed a kind of new method, the first step reaction is by the mode of re-irradiation, take NVP as raw material, reset to obtain 4-azepine ketone under light illumination, then under the existence of diaryl D-prolinol derivative, carry out Diels-Alder reaction with the chloro-crotonic aldehyde of 2-after nitrogen being protected with p-methyl benzene sulfonic chloride and build six membered ring, gained cyclohexadiene manganese dioxide dehydriding aromatize, the blocking group finally taken off on nitrogen obtains 7-chloro-2, 3, 4, 5-tetrahydro-1 H-1-benzazepino-5-ketone.

Synthesis route is as follows:

Above-mentioned technique the first step reaction NVP 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%.

Above-mentioned technique second step sulfonylation, 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-tolysulfonyl-4-azepine ketone (IV) and 2-neoprene olefine aldehydr carry out Diels-Alder reaction, obtain chloro-2,3,4,5,10, the 11-six hydrogen-1H-1-benzazepines-5-ketone (V) of N-tolysulfonyl-7-.This reaction 48 hours, yield 68%.

Above-mentioned technique the 4th step oxidative dehydrogenation: this reaction 14 hours, through heating reflux reaction, will obtain chloro-2,3,4, the 5-tetrahydro-1 H-1-benzazepino-5-ketones (VI) of N-tolysulfonyl-7-.This reaction yield 90%.

Above-mentioned technique the 5th step deprotection reaction: this reaction 12 hours, obtains chloro-2,3,4, the 5-tetrahydro-1 H-1-benzazepino-5-ketones of 7-, this reaction yield 96%.

Above-mentioned process overall yields reaches 45%.

The innovative point of this reaction is: first reset structure seven yuan of nitrogen heterocyclics by N-vinylpyridine oxazolone, then introduce six-ring, and existing seven-membered ring is built diekmann reaction used, Fu Zhongsun rearrangement reaction replaces, mild condition.

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 (0.21mol), 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 chloro-2,3,4,5,10, the 11-six hydrogen-1H-1-benzazepine-5-ketone of embodiment 3N-tolysulfonyl-7-

N-tolysulfonyl-4-azepine ketone (265mg is added in 50mL round bottom single port flask, 1.0mmol), 2-neoprene olefine aldehydr (104mg, 1.0mmol), (S)-phenylbenzene front three silica crassitude (5mg), chloroform (15ml), p-nitrobenzoic acid (5mg), room temperature reaction uses column chromatography to obtain product 238mg(0.68mmol after 48 hours), yield 68%.

¹H NMR(400MHz,CDCl ₃):δ7.73(dd,J=7.5,1.5Hz,2H),7.39(dd,J=7.5,1.5Hz,2H),5.98(dd,J=6.2,1.0Hz,1H),5.90(d,J=10.9Hz,1H),5.80(dd,J=10.9,6.2Hz,1H),3.50(dd,J=7.0,7.0Hz,1H),3.30-3.10(m,3H),2.60-2.33(m,2H),2.33(s,3H),1.97-1.86(m,2H)。

The preparation of chloro-2,3,4, the 5-tetrahydro-1 H-1-benzazepino-5-ketones of embodiment 4N-tolysulfonyl-7-

N-tolysulfonyl-7-chloro-2,3,4,5,10,11-six hydrogen-1H-1-benzazepine-5-ketone (351mg, 1.0mmol), Manganse Dioxide (1.0g) and toluene (10ml) reflux 20 hours in single port flask, cooling final vacuum concentrates, use column chromatography to obtain white solid powder 331mg(0.95mmol), yield 95%.

¹H NMR(400MHz,CDCl ₃):δ7.67(d,J=2.2Hz,1H),7.63-7.20(m,6H),3.84(t,J=6.5Hz,2H),2.43(s,3H),2.52-2.27(m,2H),2.05-1.86(m,2H)。

The preparation of chloro-2,3,4, the 5-tetrahydro-1 H-1-benzazepino-5-ketones of embodiment 57-

N-tolysulfonyl-7-chloro-2,3,4 is added after 3g polyphosphoric acid is preheating to 80-100 DEG C, 5-tetrahydro-1 H-1-benzazepino-5-ketone (350mg, 1.0mmol), then maintains same temperature and stirs 2 hours, import in frozen water, neutralize with aqueous sodium hydroxide solution and pH be adjusted to 8-9, with dichloromethane extraction, after anhydrous magnesium sulfate drying, suction filtration, concentrated, column chromatography sherwood oil: ethyl acetate (3:1) wash-out, obtains yellow solid 188mg after concentrated, yield 96%.

¹H NMR(400MHz,CDCl ₃):δ7.67(d,J=2.6Hz,1H),7.17(dd,J=8.6,2.6Hz,1H),6.70(d,J=8.6Hz,1H),4.70(brs,1H),3.33-3.10(m,2H),2.82(t,J=7.2Hz,2H),2.16(quint.,J=7.0Hz,2H)。

Claims

1. as a preparation method for the tolvaptan intermediate of structural formula I, it is characterized in that: compound V aromatize under Manganse Dioxide exists obtains compound VI; Go down to protect to obtain Compound I by compound VI in polyphosphoric acid existence;

2. preparation method according to claim 1, is characterized in that: compound IV under the existence of diaryl-D-prolinol derivative with 2-chloro-crotonic aldehyde reacting generating compound V; Described diaryl-D-prolinol derivative is (S)-2-(phenylbenzene front three silica methyl) tetramethyleneimine;

3. preparation method according to claim 2, is characterized in that: take Compound II per as raw material, reset to obtain compound III under light illumination, with Tosyl chloride, compound III acidylate is obtained compound IV;