CN102485725B - Diazacyclo bridged medicine template, preparation method thereof and application thereof - Google Patents

Diazacyclo bridged medicine template, preparation method thereof and application thereof Download PDF

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CN102485725B
CN102485725B CN201010568545.4A CN201010568545A CN102485725B CN 102485725 B CN102485725 B CN 102485725B CN 201010568545 A CN201010568545 A CN 201010568545A CN 102485725 B CN102485725 B CN 102485725B
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nonane
diaza
tertbutyloxycarbonyl
formic acid
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CN102485725A (en
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韩海涛
潘建峰
江志赶
胡滔
马汝建
陈曙辉
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Wuxi Apptec Wuhan Co Ltd
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Abstract

The invention relates to a novel diazacyclo bridged medicine template and a synthetic method thereof to solve technical problems of route lack, expensive raw material, difficult amplification, narrow applicability, and the like of compounds like the medicine template. The method comprises the following steps: 1, t-butyloxycarbonyl-4-piperidone, formaldehyde and acetic acid are heat-reacted in a solvent to obtain a diazacyclo bridged ketone compound; 2, the compound is reacted with p-methylsulfonyl methylisonitrile to convert a ketone group into a cyan group; 3, the cyan group is hydrolyzed into a carboxyl group; and 3, various protection groups are transformed through common approaches to obtain the final template 3,7- diaza[3,3,1]nonane-3-t-butyloxycarbonyl-7-benzyloxycarbonyl-9-formic acid compound (7) which is easily reacted at the third position, the seventh position and the ninth position to obtain a different substituent combined diazacyclo bridged compound (8) with the structural formula shown in the specification. The method has the advantages of high efficiency, and capability of the large scale preparation of 3,7- diaza[3,3,1]nonane-3-t-butyloxycarbonyl-7-benzyloxycarbonyl-9-formic acid.

Description

A kind of dinitrogen heterocycle bridged ring class drug template and its preparation method and application
Technical field
The present invention relates to a kind of novel dinitrogen heterocycle bridged ring class drug template, Synthesis and application.
Background technology
All the time, very large proportion is occupied in all pharmaceutical market in cardiovascular drugs market, and constantly presents the situation of sustainable growth.Such medicine adopts fertile grace WILLIAMS-DARLING Ton (Vaughan Willims) sorting technique usually, different by its electro physiology effect, can be divided into the large class of sodium ion retarding agent, beta-blocker, potassium channel blocker, cell calcium oscillations 4.As the potassium channel blocker Antiarrhythmic Agent researched and developed, show good biological activity with 3,7-diazacyclo [3,3,1] nonane as the compound of molecule parent nucleus.Compared with traditional potassium channel blocker anti-arrhythmic, it has following advantage: 1. pharmacological action is more simple, the effective refractory period of over reach potential duration and cardiac muscular tissue mainly through blocking-up Delayed Rectifier Potassium Current (Ik) or Transient Outward Potassium Current (Ito); 2. acardia restraining effect, the effect of left chamber function even tool has some improvement, therefore on heart failure patient without significant adverse impact (US6291475B1).Dinitrogen heterocycle bridged ring class medicine attracts the eyeball of numerous researchists with its pharmacologically active remarkable out of the ordinary performance.
Just start test to this compounds and research as far back as eighties of last century the seventies and eighties researchist, as in US4451473A, researchist with two aza-bridged-ring for templated synthesis obtains a series of derivative (compound i),
And be that template has carried out a series of organism build-in test to these compounds with mouse, the data (concrete data are shown in document) surveyed and medicine lignocaine (Lidocaine) compare, in drug effect, dinitrogen heterocycle bridged ring compounds will exceed several times even tens times than the drug effect of lignocaine Lidocaine, really very attractive, but as can be seen from data also, the toxic side effect of these compounds is also larger.
The nineties has again many sections of documents to report this compounds so far; as US5468858A, researchist attempts can treat irregular pulse with dinitrogen heterocycle bridged ring class and can ease pain for stencil design synthesizes some again and have the medicine (compound of multi-functional antiarrhythmic activity (AAA active) iI),
In document, they are that model is tested a series of dinitrogen heterocycle bridged ring compounds with dog, and the data obtained and result (concrete data are shown in document) demonstrate the potentiality of this compounds as antiarrhythmic drug greatly.
And Su Wei (Solvay) company has entered III phase clinical new drug tedisamil (Tedisamil), it is also the ARR medicine for the treatment of be derived based on this medicine masterplate.
Existing III clinical trial phase of this medicine proves to reduce angina pectoris attacks frequency, effective treatment stenocardia, increase Anginal threshold, improve exercise tolerance, and have bibliographical information it clinical experimental stage by intravenous injection to patient carry out observe treat obtain data ( j. Am. Coll. Cardiol.2004,44,99-104).These data fully show that dinitrogen heterocycle bridged ring class medicine tedisamil (Tedisamil) compares very fast the action time when treatment heart disorder, and effectiveness comparison is obvious.This medicine have submitted application for quotation to U.S. FAD and Europe at present, although relevant departments propose tedisamil (Tedisamil) also need more data in secure context and drug effect, this is also enough to illustrate that dinitrogen heterocycle bridged ring compounds possesses sizable using value in medicine.
The present invention just on the basis of previous work, the drug template of the dinitrogen heterocycle bridged ring designing and synthesizing out.As template; 3; 7-diaza [3; 3; 1] nonane-3-tertbutyloxycarbonyl-7-carbobenzoxy-(Cbz)-9-formic acid has the reaction site at nearly 3 places; the various compound with antiarrhythmic activity can being prepared easily, add the diversity of such medicine, providing the selection of more horn of plenty for developing the little medicine of high reactivity side effect.Synthetic method about 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-carbobenzoxy-(Cbz)-9-formic acid does not still have bibliographical information at present, and we have attempted many routes in building-up process, and have carried out careful screening to route.Concrete route is as follows:
Route one:
In the enforcement of this synthetic route, second step reaction must first by compound 2become quaternary ammonium salt, just can carry out hydrogenation and obtain compound 3hydrochloride, and three-step reaction cannot realize in synthesis, once compound 3encounter alkaline reagents side reaction will occur cause reacting unsuccessfully.
Route two:
In the enforcement of this synthetic route, from compound 3prepare compound 4reaction in, reaction is relatively mixed and disorderly, and yield is very low, even compound 3in tertbutyloxycarbonyl change to other to the insensitive blocking group of acid, as Alloc, reaction still can not reach desirable effect, so this reaction scheme exists not easily purifying, is unfavorable for the shortcoming that the amplification etc. of reacting is many.
Route three:
In the enforcement of this synthetic route, from compound 2to compound 5preparation have good yield, regrettably from compound 5prepare compound 6reaction in, yield is very low, and this step reaction to use highly toxic product potassium cyanide, considering after amplification on there will be many inconvenience, so this route can not reach our requirement.
And the synthetic route in the present invention has higher yield, and be easy to amplify, important pharmaceutical intermediate 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-carbobenzoxy-(Cbz)-9-formic acid can be prepared in a large number from the raw material be cheaply easy to get easily 7.So the invention provides so novel important drugs intermediate, compensate for the shortcoming in this class medicinal design to a certain extent, make this medicinal compound likely obtain better pharmaceutical activity and purposes widely.
Summary of the invention
The object of the present invention is to provide a kind of simple, economical, the synthetic method of quick synthesis important drugs intermediate masterplate 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-carbobenzoxy-(Cbz)-9-formic acid.Mainly solve the technical problems such as existing synthetic route lacks and masterplate suitability is not wide.Its innovative point exists: 1, it is a novel medicine intermediate sheet intermediate; 2, starting raw material is very cheaply easy to get; 3, step is short, and yield is high; 4, purifying is simple, is easy to amplify.
Technical scheme of the present invention: a kind of dinitrogen heterocycle bridged ring class drug template: 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-carbobenzoxy-(Cbz)-9-formic acid, structural formula is as follows:
。
The synthetic method of 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-carbobenzoxy-(Cbz)-9-formic acid, comprises the following steps:
The first step: with tertbutyloxycarbonyl-4-piperidone (1) for raw material, with formaldehyde, benzylamine reacting by heating in etoh solvent obtain 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-benzyl-9-ketone ( 2);
Second step: 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-benzyl-9-ketone ( 2) with cyanating reagent to sulfonyloxy methyl methyl isocyanide react a step obtain 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-benzyl-9-cyanogen ( 3);
3rd step: 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-benzyl-9-ketone cyanogen ( 3) hydrolysis obtain 3,7-diaza [3,3,1] nonane-7-benzyl-9-formic acid ( 4);
4th step: 3,7-diaza [3,3,1] nonane-7-benzyl-9-formic acid ( 4) upper protecting group obtain 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-benzyl-9-formic acid ( 5);
5th step: 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-benzyl-9-formic acid ( 5) Deprotection obtain 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-9-formic acid ( 6);
6th step: 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-9-formic acid ( 6) upper protecting group obtain 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-carbobenzoxy-(Cbz)-9-formic acid ( 7).
Chemical equation is as follows:
。
The first step is reacted, and solvent is methyl alcohol or ethanol, preferred alcohol; Temperature of reaction is 60 ~ 80 DEG C; Reaction times is 1 ~ 3 hour.
Carry out in a solvent in second step reaction, solvent is glycol dimethyl ether or dimethyl sulfoxide (DMSO), preferred glycol dimethyl ether; And need alkalizing agent be added, alkalizing agent is sodium tert-butoxide or sodium ethylate, to add sodium ethylate for optimum condition; Temperature of reaction is-5 DEG C ~ 30 DEG C; Reaction times is 16 ~ 20 hours.
Three-step reaction carries out in a solvent, and solvent is concentrated hydrochloric acid; Temperature of reaction is 70 ~ 100 DEG C; Reaction times is 3 ~ 4 hours.
Four-step reaction carries out in a solvent, and solvent is methylene dichloride or tetrahydrofuran (THF) or water, preferably water; With sodium carbonate or triethylamine for protecting group on alkalizing agent, preferred sodium carbonate; Temperature of reaction is room temperature (20-30 DEG C); Reaction times is 2 ~ 4 hours.
5th step reaction is carried out in a solvent, and solvent is methyl alcohol, and it is catalyzer that reaction need add palladium carbon, and temperature of reaction is 45 ~ 50 DEG C; Reaction times is 24 ~ 48 hours.
Six-step process carries out in a solvent, and solvent is methylene dichloride or tetrahydrofuran (THF) or water, preferably water; With sodium carbonate or triethylamine for protecting group on alkali, preferred sodium carbonate; Temperature of reaction is room temperature (20-30 DEG C); Reaction times is 2 ~ 4 hours.
The invention has the beneficial effects as follows: 1, starting raw material is very cheaply easy to get; 2, step is short, and yield is high; 3, purifying is simple, is easy to amplify; 4, the product obtained is a novel medicine intermediate segment, 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-carbobenzoxy-(Cbz)-9-formic acid has the reaction site at nearly 3 places, can be easy to 3,7,9 are reacted, and obtain the dinitrogen heterocycle bridged ring compounds with the combination of different substituents group 8, structural formula is as follows:
The various compound with antiarrhythmic activity can being prepared easily, add the diversity of such medicine, providing the selection of more horn of plenty for developing the little medicine of high reactivity side effect.
Embodiment
Following instance contributes to understanding content of the present invention, the present invention includes but be not limited to following related content:
embodiment 1: 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-benzyl-9-ketone ( 2) synthesis technique:
60 0under C and magnetic agitation, be dissolved with in the ethanolic soln of benzylamine (54.8 grams, 0.51 mole) and paraformaldehyde (16.0 grams, 0.51 mole) to 760 milliliters and drip the ethanolic soln that 640 milliliters are dissolved with acetic acid (60.8 grams, 1.0 moles), dropwise in 2 hours.Reaction solution stirs 1 hour, adds 1080 milliliters and be dissolved with compound after cool to room temperature 1the ethanolic soln of (100.0 grams, 0.51 mole) and paraformaldehyde (19.2 grams, 0.60 mole), whole reaction solution backflow is spent the night.Then the reaction solution potassium hydroxide solution of 1 M is adjusted to pH=7.0, is spin-dried for ethanol, and aqueous phase is extracted with ethyl acetate (700 milliliters of x 3), merges organic phase, and with anhydrous magnesium sulfate drying, concentrated.Residuum column chromatography (PE:EtOAc=20:1-10:1) purifying obtains the yellow oily compound of 115 grams 2, yield 69.3%.
Proton nmr spectra (CDCl3,400 MHz), δ ppm:7.32-7.24 (m, 5 H), 4.59-4.55 (d, j=13.2 Hz, 1 H), 4.43-4.38 (d, j=13.2 Hz, 1 H), 3.51-3.44 (m, 2 H), 3.37-3.12 (m, 4 H), 2.72-2.63 (m, 2 H), 2.43-2.39 (d, j=9.6 Hz, 2 H), 1.52 (s, 9 H).
embodiment 2: 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-benzyl-9-ketone ( 2) synthesis technique:
Solvent is methyl alcohol, and temperature of reaction is backflow (60 0c), the reaction times is 10-14 hour, and all the other are identical with embodiment 1, and yield is 50%.
embodiment 3: 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-benzyl-9-nitrile ( 3) synthesis technique:
Sodium Metal 99.5 (4.1 grams, 0.18 mole) is dissolved in 75 milliliters of dehydrated alcohols, then-5 0under C and nitrogen protection, the alcohol sodium solution obtained is added drop-wise to 300 milliliters and is dissolved with compound 2in glycol dimethyl ether (DME) solution of (20.0 grams, 0.06 mole) and N-p-tolysulfonyl glycine (17.0 grams, 0.09 mole), the reaction solution room temperature for overnight obtained.Then 0 0under C, with 50 ml water cancellation reactions, and be adjusted to pH=7.0 with the dilute hydrochloric acid of 2M.Mixture is extracted with ethyl acetate (200 milliliters of x 2), merges organic phase, with anhydrous sodium sulfate drying, concentrated.Residuum column chromatography (PE:EtOAc=7:1) purifying obtains 4.0 grams of yellow solid compound 3awith 5.5 grams of yellow solid compound 3b, total recovery 46.1%.
Proton nmr spectra (compound 3a, CDCl3,400 MHz), δ ppm:7.32-7.23 (m, 5 H), 4.30-4.27 (d, j=13.2 Hz, 1 H), 4.14-4.11 (d, j=13.2 Hz, 1 H), 3.50-3.40 (m, 2 H), 3.16-3.05 (m, 2 H), 2.99-2.86 (m, 3 H), 2.66-2.63 (d, j=12.0 Hz, 2 H), 2.14 (s, 1 H), 2.07 (s, 1 H), 1.52 (s, 9 H).
Proton nmr spectra (compound 3b, CDCl3,400 MHz), δ ppm:7.33-7.22 (m, 5 H), 4.27-4.24 (d, j=14.0 Hz, 1 H), 4.09-4.06 (d, j=14.0 Hz, 1 H), 3.47-3.43 (m, 2 H), 3.37-3.34 (m, 2 H), 3.11-3.07 (dd, j=11.2 Hz, j=2.0 Hz, 1 H), 3.02-2.99 (dd, j=11.2 Hz, j=2.0 Hz, 1 H), 2.79 (s, 1 H), 2.24 (t, j=9.2 Hz, 2 H), 2.12 (s, 1 H), 2.05 (s, 1 H), 1.53 (s, 9 H).
embodiment 4: 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-benzyl-9-nitrile ( 3) synthesis technique:
Under room temperature (25 0c), add alcohol sodium solution, temperature of reaction is 25 0c, the reaction times is 16 hours, and all the other are identical with embodiment 3, total recovery 32%.
embodiment 5: 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-benzyl-9-nitrile ( 3) synthesis technique:
Solvent is glycol dimethyl ether, and alkalizing agent is sodium tert-butoxide, and temperature of reaction is room temperature (25 0c), the reaction times is 12-15 hour, and all the other are identical with embodiment 3, and total recovery is 30%.
embodiment 6: 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-benzyl-9-nitrile ( 3) synthesis technique:
Solvent is dimethyl sulfoxide (DMSO), and alkalizing agent is sodium tert-butoxide, and temperature of reaction is room temperature (25 0c), the reaction times is 12-15 hour, and all the other are identical with embodiment 3, and total recovery is 20%.
embodiment 7: 3,7-diaza [3,3,1] nonane-7-benzyl-9-formic acid ( 4) synthesis technique:
By compound 3awith 3b(11.0 grams, 0.032 mole) are dissolved in the concentrated hydrochloric acid of 100 milliliters 37%, and solution is 110 0reflux 3 hours under C, be spin-dried for the crude product P-HPLC obtained and be separated, obtain 4.0 grams of compound as white solid 4awith 3.0 grams of compound as white solid 4b, total recovery 73.0%.
Proton nmr spectra (compound 4a, CD 3oD, 400 MHz), δ ppm:7.37-7.28 (m, 5 H), 3.58-3.52 (m, 4 H), 3.35-3.32 (m, 2 H), 3.06-3.03 (d, j=10.8 Hz, 2 H), 2.90 (s, 1 H), 2.60-2.57 (m, 4 H).
Proton nmr spectra (compound 4b, CD 3oD, 400 MHz), δ ppm:7.40-7.30 (m, 5 H), 3.61 (s, 2 H), 3.43-3.33 (m, 4 H), 3.26-3.23 (d, j=9.6 Hz, 2 H), 2.77 (s, 1 H), 2.56-2.50 (m, 4 H).
embodiment 8: 3,7-diaza [3,3,1] nonane-7-benzyl-9-formic acid ( 4) synthesis technique:
Solvent is the hydrochloric acid of 6 mol/L, and temperature of reaction is backflow (110 0c), the reaction times is 12-14 hour, and all the other are identical with embodiment 7, and total recovery is 50%.
embodiment 9: 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-benzyl-9-formic acid ( 5a) synthesis technique:
0 0c, is dissolved with compound to 40 milliliters 4aadd sodium carbonate (2.73 grams, 0.026 mole) and tert-Butyl dicarbonate (3.5 grams, 0.016 mole) in the aqueous solution of (4.0 grams, 0.013 mole), the reaction solution obtained at room temperature stirs and spends the night.Then reaction solution is extracted with ethyl acetate (20 milliliters of x 2), and aqueous phase 1M dilute hydrochloric acid is adjusted to pH=5.0, is extracted with ethyl acetate (30 milliliters of x 3), the organic phase anhydrous sodium sulfate drying of merging, is spin-dried for and obtains 4.5 grams of compound as white solid 5a, yield 92.5%.
Proton nmr spectra (CD 3oD, 400 MHz), δ ppm:7.52-7.50 (m, 5 H), 4.30 (s, 2 H), 4.14-4.10 (d, j=13.2 Hz, 2 H), 3.55-3.52 (d, j=13.2 Hz, 2 H), 3.38-3.35 (d, j=13.2 Hz, 2 H), 3.20-3.17 (d, j=13.2 Hz, 2 H), 2.83 (s, 1 H), 2.65 (br s, 2 H), 1.53 (s, 9 H).
embodiment 10: 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-benzyl-9-formic acid ( 5b) synthesis technique:
React identical with embodiment 9, with the compound of 3.0 grams 4bobtain 3.5 g of compound 5b, yield 96.1%.
Proton nmr spectra (CD 3oD, 400 MHz), δ ppm:7.54 (br s, 5 H), 4.38 (s, 2 H), 3.93-3.90 (d, j=13.2 Hz, 2 H), 3.71-3.67 (d, j=13.2 Hz, 2 H), 3.44-3.41 (d, j=13.2 Hz, 2 H), 0.23-3.20 (d, j=13.2 Hz, 2 H), 2.94 (s, 1 H), 2.69 (br s, 2 H), 1.51 (s, 9 H).
embodiment 11: 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-benzyl-9-formic acid ( 5a) synthesis technique:
Reaction solvent is methylene dichloride, and alkalizing agent is triethylamine, and temperature of reaction is 25 0c, the reaction times is 10 hours, and all the other are identical with embodiment 9, and yield is 85%.
embodiment 12: 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-benzyl-9-formic acid ( 5a) synthesis technique:
Reaction solvent is tetrahydrofuran (THF), and alkalizing agent is sodium carbonate, and temperature of reaction is 25 0c, the reaction times is 5 hours, and all the other are identical with embodiment 9, and yield is 80%.
embodiment 13: 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-9-formic acid ( 6) synthesis technique:
5.0 g of compound are dissolved with to 50 milliliters 5methanol solution in add 0.5 gram of specification be the palladium-carbon catalyst of 10%, it is 45 psi that the reaction solution obtained is placed in hydrogen pressure, and temperature is 50 0stir 6 hours under the condition of C.Filter catalyzer, filtrate is directly spin-dried for and obtains 3.5 g of compound 6, yield 93.6%.
embodiment 14:3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-9-formic acid ( 6) synthesis technique:
Reaction solvent is ethanol, and hydrogen pressure is 35 psi, and temperature of reaction is 40 0c, the reaction times is 24-48 hour, yield 80%.
embodiment 15: 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-carbobenzoxy-(Cbz)-9-formic acid ( 7) synthesis technique:
0 0c, is dissolved with 2.0 g of compound to 30 milliliters 6the aqueous solution in add sodium carbonate (1.6 grams, 0.015 mole) and chloroformic acid benzyl ester (1.4 grams, 0.008 mole), the reaction solution obtained was stirring at room temperature 3 hours.Reaction solution ethyl acetate washs secondary, and then reaction solution 1M dilute hydrochloric acid is adjusted to pH=5.0, is extracted with ethyl acetate three times, combining extraction liquid, obtains 2.7 grams of compound as white solid after being spin-dried for 7, yield 90.3%.
Proton nmr spectra (CD 3oD, 400 MHz), δ ppm:7.38-7.32 (m, 5 H), 5.12-4.98 (m, 2 H), 4.30 (t, j=13.2 Hz, 2 H), 4.08 (t, j=13.2 Hz, 2 H), 3.37-3.04 (m, 4 H), 2.78 (s, 1 H), 2.387-2.30 (m, 2 H), 1.46-1.38 (m, 9 H).
embodiment 16: 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-carbobenzoxy-(Cbz)-9-formic acid ( 7) synthesis technique:
Reaction solvent is methylene dichloride, and alkalizing agent is triethylamine, and temperature of reaction is room temperature (25 0c), the reaction times is 12-16 hour, yield 85%.
embodiment 17: 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-carbobenzoxy-(Cbz)-9-formylaniline ( 8) synthesis technique:
0 0c, is dissolved with 200 milligrams of compounds to 10 milliliters 7dichloromethane solution in add aniline (50 milligrams successively, 0.54 mmole), triethylamine (75 milligrams, 0.74 mmole), I-hydroxybenzotriazole (80 milligrams, 0.60 mmole) and 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (115 milligrams, 0.60 mmole), the reaction solution obtained was stirring at room temperature 3 hours.Then reaction solution is spin-dried for solvent after washing secondary with water, and residuum is purified by preparative chromatography plate and obtained 425 milligrams of compound as white solid 8, yield 85.6%.
embodiment 18: 3,7-diaza [3,3,1] nonane-3-ethamine carbonyl-7-carbobenzoxy-(Cbz)-9-formylaniline ( 9) synthesis technique:
0 0c, by 200 milligrams of compounds 8be dissolved in the hydrogen chloride methanol solution of 20 milliliters of 4M, then at room temperature stir half hour, be spin-dried for solvent.Residuum is dissolved in 20 milliliters of methylene dichloride, 0 0c adds triethylamine (85 milligrams, 0.84 mmole) and ethyl isonitrile acid esters (36 milligrams, 0.50 mmole), and the reaction solution obtained was stirring at room temperature 2 hours.Then reaction solution is spin-dried for solvent after washing secondary with water, and residuum is purified by preparative chromatography plate and obtained 151 milligrams of compound as white solid 9, yield 80.2%.
embodiment 19: 3,7-diaza [3,3,1] nonane-3-ethamine carbonyl-7-cyclopentyl-9-formylaniline ( 10) synthesis technique:
Under nitrogen protection, the palladium carbon of 30 milligram 10% is added to 20 milliliters and is dissolved with 151 milligrams of compounds 9methanol solution in, then reaction solution stirred at ambient temperature 3 hours under hydrogen balloon, falls palladium carbon with diatomite filtration, is spin-dried for filtrate.Residuum is dissolved in 20 ml methanol, adds cyclopentanone (42 milligrams, 0.50 mmole) and sodium cyanoborohydride (32 milligrams, 0.50 mmole), the reaction solution obtained, stirring at room temperature 2 hours, revolves and steams removing methyl alcohol, add 20 milliliters of methylene dichloride and 20 ml waters.Aqueous phase dichloromethane extraction three times, merges organic phase, is spin-dried for solvent with after anhydrous sodium sulfate drying, and residuum is purified by preparative chromatography plate and obtained 79.5 milligrams of compound as white solid 10, yield 61.7%.

Claims (1)

  1. The synthetic method of 1.3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-carbobenzoxy-(Cbz)-9-formic acid, comprises the following steps:
    The first step is reacted, and with tertbutyloxycarbonyl-4-piperidone for raw material, with formaldehyde, benzylamine in a solvent reacting by heating obtains compound 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-benzyl-9-ketone; The first step reaction solvent is ethanol, and temperature of reaction is 60 ~ 80 DEG C; Reaction times is 3 ~ 4 hours;
    Second step reacts, and 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-benzyl-9-ketone and cyanating reagent react a step to sulfonyloxy methyl methyl isocyanide and obtain 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-benzyl-9-nitrile; Second step reaction is carried out in solvent ethylene glycol dme, and need add alkalizing agent sodium ethylate, and temperature of reaction is-5 DEG C ~ 30 DEG C; Reaction times is 16 ~ 20 hours;
    Three-step reaction, the hydrolysis of 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-benzyl-9-nitrile obtains 3,7-diaza [3,3,1] nonane-7-benzyl-9-formic acid; Three-step reaction carries out in solvent concentrated hydrochloric acid, and temperature of reaction is 70 ~ 100 DEG C; Reaction times is 3 ~ 4 hours;
    Four-step reaction, on 3,7-diaza [3,3,1] nonane-7-benzyl-9-formic acid, protecting group obtains 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-benzyl-9-formic acid; Four-step reaction carries out in water, take sodium carbonate as protecting group on alkalizing agent, and temperature of reaction is room temperature; Reaction times is 2 ~ 4 hours;
    5th step reaction, 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-benzyl-9-formic acid Deprotection obtains 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-9-formic acid; 5th step reaction is carried out in solvent methanol, and it is catalyzer that reaction need add palladium carbon, and temperature of reaction is 45 ~ 50 DEG C; Reaction times is 5 ~ 7 hours;
    Six-step process, on 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-9-formic acid, protecting group obtains 3,7-diaza [3,3,1] nonane-3-tertbutyloxycarbonyl-7-carbobenzoxy-(Cbz)-9-formic acid; Six-step process carries out in water, take sodium carbonate as protecting group on alkalizing agent, and temperature of reaction is room temperature; Reaction times is 2 ~ 4 hours.
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