CN103073472B - The preparation method of the azacycloparaffin of 2 trifluoromethyl, 1 benzyloxycarbonyl group 1 - Google Patents
The preparation method of the azacycloparaffin of 2 trifluoromethyl, 1 benzyloxycarbonyl group 1 Download PDFInfo
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- CN103073472B CN103073472B CN201310014043.0A CN201310014043A CN103073472B CN 103073472 B CN103073472 B CN 103073472B CN 201310014043 A CN201310014043 A CN 201310014043A CN 103073472 B CN103073472 B CN 103073472B
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Abstract
The invention discloses a kind of preparation method of the azacycloparaffin of 2 trifluoromethyl, 1 benzyloxycarbonyl group 1.Mainly solution prepares the α position trifluoromethyl azacycloparaffins step length of nitrogen, the problems such as yield is low.The present invention is using the ketone of azacycloparaffin 2 as initiation material; protect to obtain the azacycloparaffin of 2 oxa-, 1 benzyloxycarbonyl group 1 by Cbz; again by reacting to obtain the azacycloparaffin of 2 hydroxyl, 2 trifluoromethyl, 1 benzyloxycarbonyl group 1 with trifluoromethyl reagent, the hydrogenated deprotection of gained compound obtains the azacycloparaffin of 2 trifluoromethyl, 1 benzyloxycarbonyl group 1.Total recovery is 13~35.8%.
Description
Technical field
The present invention relates to a kind of preparation method of 2- Trifluoromethyl-1s-benzyloxycarbonyl group -1- azacycloparaffins.
Background technology
The azacycloparaffin of nitrogen-alpha-substituted is a kind of important nitrogen heterocyclic ring, except some exist in natural products, it
And the miscellaneous beneficial group with multiple biological activities of structure.This kind of heterocycle has the feature of many alkaloids,
Many documents once reported the compound containing this kind of heterocycle in clinical or preclinical study.This kind of compound is that a class formation is more special
Different molecule, can by key pharmacophore unit effectively connection be incorporated into its rigid structure, formed have special space configuration/
The molecule of conformation, so as to match the space structure of different large biological molecules in organism, produce different bioactivity or effect
With.Up to now compound research of the nitrogen-α positions containing trifluoromethyl it is also few, and the research of fluorochemical also result in
The extensive concern of people, a kind of easy method of comparison is described herein and carrys out compound of the synthetic nitrogen-α positions containing trifluoromethyl, with
The electronic effect and three-dimensional effect of phase change molecular structure improve the purpose of its quasi-medicated property matter to reach.
Article《Synthesis》（Synthesis 2010, No. 1, 120-126）In also report nitrogen-α positions and contain trifluoromethyl
Compound synthesis.By raw material lactams, via hydrolysis, decarboxylation, formation half amide sloughs one again in the basic conditions
Molecular water most obtains the fluorine-containing compound in nitrogen-α positions through reduction afterwards so as to form fluorine-containing epimino.This method prepares alpha-substituted
Azacycloparaffin step is grown, and yield is low, low to 10% especially for azepan yield.Thus this method is not suitable for anti-
The amplification answered, there is suitable limitation.
。
Article pharmaceutical chemistry magazine（J. Med. Chem. 1999, 42, 3315-3323）Report a series of nitrogen-α-
Research of the compound of trifluoromethyl to the inhibitor of phenylethanol amine-n-transmethylase.It is notable by introducing trifluoromethyl
The selectivity to PNMT inhibitor is improved, while also causes the lipophilicity of compound to have at a relatively high raising.It is new to develop
High selectivity inhibitor PNMT provide new up-and-coming clue, while there is very high lipophilicity with penetration rate of blood brain
Barrier.
Article biological organic and pharmaceutical chemistry bulletin（Bioorganic & Medicinal Chemistry Letters
17 (2007) 4328–4332）Also the different substituents group of the compound containing nitrogen-α-trifluoromethyl is reported to histone
The research of enzyme K selectivity.
Therefore fluoro-containing group, as the compound of α-trifluoromethyl can largely effect on the polarity, solubility, chemistry of compound
Reactivity simultaneously influences the interaction of whole molecule.It is a kind of important medicine intermediate in the α position trifluoromethyls of nitrogen, it is right
Medicine, agricultural chemicals, organic material have a wide range of applications.
The content of the invention
The purpose of the present invention is to be to provide a kind of system of new 2- Trifluoromethyl-1s-benzyloxycarbonyl group -1- azacycloparaffins
Preparation Method.Mainly solution prepares the α position trifluoromethyl azacycloparaffins step length of nitrogen, the problems such as yield is low.Present invention reduces
The step of preparing the α position trifluoromethyl azacycloparaffins of nitrogen, three steps are reduced to by six steps.Total yield significantly improves, especially
The total recovery of the α position trifluoromethyl azepans of nitrogen brings up to 35.8%.
Technical scheme is：Such as formula（I）The preparation method of shown 2- Trifluoromethyl-1s-benzyloxycarbonyl group -1- azacycloparaffins.It is main
Want reaction equation as follows：
Formula（I）
It is characterized in that with azacycloparaffin -2- ketone (1a-1c) for initiation material, protect to obtain 2- oxa-s -1- by Cbz
Benzyloxycarbonyl group -1- azacycloparaffins (2a-2c), then by reacting to obtain 2- hydroxyl -2- fluoroforms with trifluoromethyl reagent
Base -1- benzyloxycarbonyl group -1- azacycloparaffins (3a-3c), the hydrogenated deprotection of gained compound obtain 2- Trifluoromethyl-1s-benzyl
Oxygen carbonyl -1- azacycloparaffins（I-III）.Total recovery is 13~35.8%.
Wherein, compound 1 and amido protecting agent, in the presence of alkaline matter, reaction gained chemical combination in organic solvent
Thing 2, amido protecting agent used are benzyl chloroformate；Alkaline matter used is n-BuLi, and solvent used is tetrahydrochysene
Furans.
Compound 2 and alkaline matter, trifluoromethyl trimethyl silicane reaction gained compound 3, alkaline matter used is fluorine
Change one kind in caesium, tetrabutyl amine fluoride, sodium fluoride, potassium fluoride, using sodium fluoride as optimum condition；Solvent used is tetrahydrochysene furan
Mutter, acetonitrile, dioxane,N,N- dimethylformamide,N,N- dimethyl acetamide,N,N- diethylformamide, dimethyl are sub-
Sulfone,NOne or more of mixed solvents in-methyl pyrrolidone, using acetonitrile as optimum condition.Reaction time used preferably 3 is small
When.
Compound 4 obtained by the hydro-reduction of compound 3, catalyst used is palladium carbon, palladium black, platinum dioxide, rhodium carbon, wherein
Using palladium carbon as optimum condition；Hydrogen Vapor Pressure used is normal pressure to 10 atmospheric pressure.Solvent for use is methanol, ethanol, isopropanol, third
One kind in alcohol, tetrahydrofuran, dioxane, ethyl acetate.Using tetrahydrofuran as optimum condition.25 DEG C of preferable reaction temperature；
Reaction time used is preferably 10 hours.
Beneficial effects of the present invention：The present invention introduces three by 3 steps from cheap azacycloparaffin -2- ketone at 1
Methyl fluoride, further improve its quasi-medicated property matter to change the electronic effect of molecular structure and three-dimensional effect.We provide system
The method of such standby compound.Existing document《Synthesis》（Synthesis2010, 120-126）Report nitrogen-α positions and contain fluoroform
The synthesis of the compound of base.By raw material lactams, via hydrolysis, decarboxylation, formation half amide is sloughed again in the basic conditions
One molecular water most obtains the fluorine-containing compound in nitrogen-α positions through reduction afterwards so as to form fluorine-containing epimino.This method preparation α-take
Grown for azacycloparaffin step, yield is low, low to 10% especially for the α position trifluoromethyl azepan yields of nitrogen.Thus
This method is not suitable for the amplification of reaction, has suitable limitation.Present invention reduces prepare alpha-substituted azacycloparaffin
Step, three steps are reduced to by six steps.Total yield significantly improves, especially total receipts of the α position trifluoromethyl azepans of nitrogen
Rate brings up to 35.8%.
Embodiment
Embodiment 1：It is prepared by 2- oxa-s-benzyloxycarbonyl group cycloheptylamine 2c
Operating procedure：
Nitrogen protection under, in a dry three-necked bottle add compound cycloheptyl acid amides 1c (20 grams, 0.23 mole) and
Tetrahydrofuran (200 milliliters), n-BuLi is slowly added under dry ice acetone bath, and (94 milliliters, 0.23 mole, 2.5 M are just
Hexane solution).Reaction solution stirs 60 minutes at -78 DEG C, is then slowly added into benzyl chloroformate（40 grams, 0.23 mole）Four
Hydrogen furans (50 milliliters) solution.Stirring 10 hours is slowly warmed to room temperature, is quenched with saturated aqueous ammonium chloride, uses ethyl acetate
Extraction, organic phase are dried and are concentrated to give 53 grams of product 2- oxa-s-benzyloxycarbonyl group cycloheptylamine 2c, yield 100%.It is directly used in next step
Reaction.
Embodiment 2：It is prepared by 2- oxa- -1- benzyloxycarbonyl group pyrrolins 2a
During n=1, same embodiment 1 is operated.Yield 100%.It is directly used in and reacts in next step.
Embodiment 3：It is prepared by 2- oxa- -1- Benzyloxycarbonylpiperidins 2b
During n=2, same embodiment 1 is operated.Yield 70%.It is directly used in and reacts in next step.
Embodiment 4：2- hydroxyls -2- Trifluoromethyl-1s-benzyloxycarbonyl group cycloheptylamine 3c preparation
Operating procedure：
Under nitrogen protection, 2- oxa-s -1- benzyloxycarbonyl groups-cycloheptylamine 2c (3 grams, 13.6 mMs) is dissolved in anhydrous
In tetrahydrofuran (30 milliliters), cesium fluoride is added（0.93 gram, 6.12 mMs）With trifluoromethyl trimethyl silicane (5.8 grams,
41.1 mM).The reaction solution is stirred at room temperature 3 hours, TLC tracking reactions (petrol ether/ethyl acetate volume ratio=3:1),
After terminating Deng reaction, add that water is overworked goes out, be extracted with ethyl acetate, organic phase dries concentration, is obtained by silica gel column chromatography
2.5 grams of 2- hydroxyls-2- Trifluoromethyl-1-benzyloxycarbonyl group-cycloheptylamine 3c, yield 39%.
Embodiment 5：2- hydroxyls -2- Trifluoromethyl-1s-benzyloxycarbonyl group cycloheptylamine 3c preparation
Operating procedure：
Under nitrogen protection, 2- oxa-s -1- benzyloxycarbonyl groups-cycloheptylamine 2c (3 grams, 13.6 mMs) is dissolved in anhydrous
In tetrahydrofuran (30 milliliters), tetrabutyl ammonium fluoride is added（1.96 grams, 6.12 mMs）With trifluoromethyl trimethyl silicane
(5.8 grams, 41.1 mMs).The reaction solution is stirred at room temperature 3 hours, TLC tracking reaction (petrol ether/ethyl acetate volumes
Than=3:1) after, waiting reaction to terminate, add that water is overworked goes out, be extracted with ethyl acetate, organic phase dries concentration, by silica gel column chromatography
Obtain 2.5 grams of 2- hydroxyls-2- Trifluoromethyl-1-benzyloxycarbonyl group-cycloheptylamine 3c, yield 28%.
Embodiment 6：2- hydroxyls-2- Trifluoromethyl-1-benzyloxycarbonyl groups-pyrrolin 3a
During n=1, alkaline matter is that sodium fluoride replaces tetrabutyl ammonium fluoride, and solvent is that acetonitrile replaces tetrahydrofuran, and operation is same
Embodiment 5.Yield 64%.1H NMR (400MHz, CDCl3): 7.31 (s, 5 H), 5.05-5.20 (m, 2 H),
3.65-3.72 (m, 1 H), 3.46-3.52 (m, 1 H), 2.34-2.41 (m, 1 H), 2.04-2.11 (m, 1
H), 1.82-1.98 (m, 2 H).Anal. Calcd. for C13H14F3NO3 (MS [M+H]+: 290.0999),
Measured Mass: 290.0996.error:-0.84 ppm。
Embodiment 7：2- hydroxyls -2- Trifluoromethyl-1s-BenzvIoxvcarbonvl-piperidin 3b
During n=2, solvent isN,N- dimethylformamide replaces tetrahydrofuran, operates same embodiment 5.Yield：38%.Directly
For reacting in next step.
Embodiment 8：2- Trifluoromethyl-1s-benzyloxycarbonyl group-cycloheptylamine（III）Preparation
Operating procedure：
2- hydroxyls -2- Trifluoromethyl-1s-benzyloxycarbonyl group cycloheptylamine 3 (1 gram, 3.46 mMs) are dissolved in tetrahydrofuran
In (20 milliliters), wet palladium carbon is added（0.5 g, 10w%）, 25oC stirring reactions 10 under the Hydrogen Vapor Pressure of 1 atmospheric pressure are small
When.Reaction solution is filtered to remove palladium carbon, and sodium acid carbonate is added in mother liquor（0.623 gram, 6.92 mMs）And water（10 milliliters）,
Add benzyl chloroformate.Stirring reaction 2 hours.It is extracted with ethyl acetate, organic phase dries concentration, by silica gel column chromatography
Obtain 0.5 gram of 2- Trifluoromethyl-1s-benzyloxycarbonyl group-cycloheptylamine (III), yield 61%.1H NMR (400MHz, CDCl3):
7.24-7.30 (m, 5 H), 5.08-5.12 (m, 2 H), 4.65-4.74 (m, 0.5 H), 4.47-4.54 (m,
0.5 H),3.82-3.95 (m, 1 H), 2.81-2.89 (m, 1 H), 2.09-2.24 (m, 1 H), 1.78-1.87
(m, 2 H), 1.34-1.71 (m, 3 H),1.12-1.25 (m, 2 H).Anal. Calcd. for C15H18F3NO2
(MS [M+Na]+: 324.1182), Measured Mass: 324.1202.error:-6.24 ppm。
Embodiment 9：2- Trifluoromethyl-1s-benzyloxycarbonyl group-pyrrolin (I)
During n=1, the catalyst of hydro-reduction is that platinum dioxide replaces wet palladium carbon, and solvent is that ethanol replaces tetrahydrofuran,
Operation is the same as embodiment 8.Yield 56%.1H NMR (400MHz, CDCl3): 7.24-7.35 (m, 5 H), 5.11-5.19
(m, 2 H), 4.44-4.49 (m, 1 H), 3.45-3.61 (m, 2 H), 1.90-2.08 (m, 4 H).Anal.
Calcd. for C13H14F3NO2 (MS [M+Na]+: 296.0869), Measured Mass:
296.0863.error:-1.9 ppm。
Embodiment 10:2- trifluoromethyls-Benzyloxycarbonylpiperidin (II)
During n=2, the catalyst of hydro-reduction is that rhodium carbon replaces wet palladium carbon, and solvent is that dioxane replaces tetrahydrofuran,
Operation is the same as embodiment 8.Yield 50%.1H NMR (400MHz, CDCl3): 7.28 (s, 5 H), 5.09 (s, 2 H),
4.62-4.78 (m, 1 H), 4.09-4.14 (m, 1 H), 2.85-3.00 (m, 1 H), 1.90-1.98 (m, 1
H), 1.55-1.60 (m, 4 H), 1.30-1.40 (m, 1 H).Anal. Calcd. for C14H16F3NO2 (MS
[M+H]+: 288.1206), Measured Mass: 288.1200.error:-1.88 ppm。
Claims (5)
- The preparation method of 1.2- Trifluoromethyl-1s-benzyloxycarbonyl group -1- azacycloparaffins, it is characterized in that, comprise the following steps：The first step：Using azacycloparaffin -2- ketone as initiation material, under the conditions of n-BuLi, in solvents tetrahydrofurane with chlorine Benzyl formate reacts to obtain 2- oxa- -1- benzyloxycarbonyl group -1- azacycloparaffins；Second step：2- oxa- -1- benzyloxycarbonyl group -1- azacycloparaffins under the conditions of alkali compounds, in a solvent with fluoroform Base reagent reacting obtains 2- hydroxyls -2- Trifluoromethyl-1s-benzyloxycarbonyl group -1- azacycloparaffins；Alkaline matter used is fluorine Change one kind in caesium, tetrabutyl amine fluoride, sodium fluoride, potassium fluoride；Solvent used be tetrahydrofuran, acetonitrile, dioxane,N,N- dimethylformamide,N,N- dimethyl acetamide,N,N- diethylformamide, dimethyl sulfoxide (DMSO),NIn-methyl pyrrolidone One or more of mixed solvents；3rd step：2- hydroxyls -2- Trifluoromethyl-1s-benzyloxycarbonyl group -1- azacycloparaffins are under metallic catalyst catalysis, organic 2- trifluoromethyl azacycloparaffins are obtained with hydrogen reducing in solvent, then react with acylting agent to obtain 2- fluoroforms again Base -1- benzyloxycarbonyl group -1- azacycloparaffins；Catalyst used is one kind in palladium carbon, palladium black, platinum dioxide, rhodium carbon；It is used Organic solvent is one kind in methanol, ethanol, isopropanol, propyl alcohol, tetrahydrofuran, dioxane or ethyl acetate；Reaction equation is as follows：。
- 2. the preparation method of 2- Trifluoromethyl-1s according to claim 1-benzyloxycarbonyl group-1- azacycloparaffins, its feature It is that the reaction time used in the first step is 10 hours.
- 3. the preparation method of 2- Trifluoromethyl-1s according to claim 1-benzyloxycarbonyl group-1- azacycloparaffins, its feature It is that the alkaline matter used in second step is sodium fluoride, solvent used is acetonitrile.
- 4. the preparation method of 2- Trifluoromethyl-1s according to claim 1-benzyloxycarbonyl group-1- azacycloparaffins, its feature It is that the Hydrogen Vapor Pressure used in three-step reaction is normal pressure to 10 atmospheric pressure.
- 5. the preparation method of 2- Trifluoromethyl-1s according to claim 1-benzyloxycarbonyl group-1- azacycloparaffins, its feature It is that the catalyst used in the three-step reaction is palladium carbon, solvent for use is tetrahydrofuran.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3748341A (en) * | 1968-08-13 | 1973-07-24 | Scient Et Ind De I Iie De Fr S | Process of preparing 1-substituted-2-aminomethylpyrrolidines and intermediates therefor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3748341A (en) * | 1968-08-13 | 1973-07-24 | Scient Et Ind De I Iie De Fr S | Process of preparing 1-substituted-2-aminomethylpyrrolidines and intermediates therefor |
Non-Patent Citations (2)
| Title |
|---|
| A simple one-pot synthesis of α-trifluoromethyl-substituted enamines by C-trifluoromethylation of dialkylamides with P(NEt2)3/CF3Br;Hans Buirger，et al.;《Journal of Fluorine Chemistry》;19951231(第70期);第89-93页 * |
| Practical Synthesis of a-Perfluoroalkyl Cyclic Imines and Amines;Nikolay E.Shevchenko，et al.;《Synthesis》;20101231(第1期);第120-126页 * |
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