CN109879797A - N- benzyl-tetrahydropyridines and preparation method thereof - Google Patents
N- benzyl-tetrahydropyridines and preparation method thereof Download PDFInfo
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- CN109879797A CN109879797A CN201910021522.2A CN201910021522A CN109879797A CN 109879797 A CN109879797 A CN 109879797A CN 201910021522 A CN201910021522 A CN 201910021522A CN 109879797 A CN109879797 A CN 109879797A
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Abstract
The present invention provides a kind of N- benzyl-tetrahydropyridines and preparation method thereof, and preparation method includes the following steps: step S1, and benzyl bromine is added in pyridine compounds and their, and nucleophilic substitution occurs, obtains pyridiniujm；Step S2 makes the pyridiniujm and reducing agent that reduction reaction occur, obtains the N- benzyl-tetrahydropyridines.The present invention is by proper choice of reducing agent and setting reaction route, and especially when being that reducing agent obtains target compound using potassium borohydride, reaction condition is mild, reaction selectivity is high, and by-product is few, easy to operate, total recovery is higher, and the feasibility of route is stronger, is easy to industrialized production.
Description
Technical field
The invention belongs to the synthesis of the pharmaceutical chemistry of organic chemistry filed, and in particular to N- benzyl-tetrahydropyridines
And preparation method thereof.
Background technique
N- benzyl-tetrahydropyridines are a kind of important heterocyclic intermediates, have good biology and medicinal valence
Value, thus have wide application value in medical research.
Currently, the N- benzyl-tetrahydropyridines of report synthesis both at home and abroad react more violent in synthesis, it is right
Reaction temperature requires harshness, and side reaction is more, and obtained product yield is lower, impurity is more.These disadvantages all give its industrialized production
It makes troubles.
Summary of the invention
In view of this, the present invention provides a kind of reaction condition mild, easy to operate, suitable for industrialized production N- benzyl
Base-tetrahydropyridines preparation method.
The present invention also provides a kind of N- benzyl-tetrahydropyridines
In order to solve the above technical problems, the invention adopts the following technical scheme:
The preparation method of N- benzyl-tetrahydropyridines according to an embodiment of the present invention, which is characterized in that including
Following steps:
Benzyl bromine is added in step S1 in pyridine compounds and their, and nucleophilic substitution occurs, obtains pyridiniujm；
Step S2 makes the pyridiniujm and reducing agent that reduction reaction occur, obtains the N- benzyl-tetrahydropyridine class
Compound.
According to some embodiments of the present invention, the step S1 includes:
Step S11, the pyridine compounds and their is dispersed in the first organic solvent, be added wherein the benzyl bromine with
Nucleophilic substitution occurs, obtains the pyridiniujm, first organic solvent be acetone, tetrahydrofuran, acetonitrile, toluene,
Or mixtures thereof.
Further, the step S1 further include:
Step S12 carries out cooling after the completion of reaction, filters and dry to refine to the pyridiniujm.
Optionally, the molar ratio of the pyridine compounds and their and the benzyl bromine is 1.0:1.0~1.5, reaction temperature 20
~90 DEG C, the reaction time is 4~20h.
According to some embodiments of the present invention, the step S2 includes:
Step S21, by the pyridiniujm dispersion in a second organic solvent, and be added wherein the reducing agent with
Occur reduction reaction, wherein second solvent be anhydrous methanol, dehydrated alcohol, or mixtures thereof.
Optionally, the step S2 further include:
Step S22 is evaporated, is extracted, is dried, is evaporated again after the completion of reaction, the N- benzyl-refined
Tetrahydropyridines.
According to some embodiments of the present invention, the reducing agent is or mixtures thereof potassium borohydride, sodium borohydride.
Preferably, the reducing agent is potassium borohydride.
According to some embodiments of the present invention, the ratio between mole of the pyridiniujm and the reducing agent is 1.0:1.0
~4.0, reaction temperature is -10~-5 DEG C, and the reaction time is 3~6h.
The present invention also provides the N- being prepared according to preparation method described in any of the above embodiments benzyl-tetrahydropyridine classes
Compound.
The present invention is being especially reduction using potassium borohydride by proper choice of reducing agent and setting reaction route
When agent obtains target compound, reaction condition is mild, and reaction selectivity is high, and by-product is few, and easy to operate, total recovery is higher, road
The feasibility of line is stronger, is easy to industrialized production.
Specific embodiment
In order to make the object, technical scheme and advantages of the embodiment of the invention clearer, below to the skill of the embodiment of the present invention
Art scheme is clearly and completely described.Obviously, described embodiment is a part of the embodiments of the present invention, rather than complete
The embodiment in portion.Based on described the embodiment of the present invention, those of ordinary skill in the art's every other implementation obtained
Example, shall fall within the protection scope of the present invention.
In conjunction with following specific embodiments, the present invention is described in further detail.Implement process of the invention, condition,
Experimental method etc. is among the general principles and common general knowledge in the art in addition to what is specifically mentioned below, and the present invention does not have
There is especially limitation content.
The preparation method of N- benzyl-tetrahydropyridines according to an embodiment of the present invention, includes the following steps:
Benzyl bromine is added in step S1 in pyridine compounds and their (hereinafter sometimes referred to as compound I), and it is anti-that nucleophilic displacement of fluorine occurs
It answers, obtains pyridiniujm (hereinafter sometimes referred to as compound II).
Shown in its reaction process such as following formula (1).
According to some embodiments of the present invention, the step S1 may include:
Step S11, the pyridine compounds and their is dispersed in the first organic solvent, be added wherein the benzyl bromine with
Nucleophilic substitution occurs, obtains the pyridiniujm, first organic solvent be acetone, tetrahydrofuran, acetonitrile, toluene,
Or mixtures thereof.
Optionally, the molar ratio of the pyridine compounds and their and the benzyl bromine is 1.0:1.0~1.5, reaction temperature 20
~90 DEG C, the reaction time is 4~20h.
Further, the step S1 can also include:
Step S12 carries out cooling after the completion of reaction, filters and dry to refine to the pyridiniujm.
Step S2 makes the pyridiniujm (i.e. compound II) and reducing agent that reduction reaction occur, obtains the N- benzyl
Base-tetrahydropyridines (hereinafter referred to as compound III).
Shown in its reaction process such as following formula (2).
According to some embodiments of the present invention, the step S2 includes:
Step S21, by the pyridiniujm dispersion in a second organic solvent, and be added wherein the reducing agent with
Occur reduction reaction, wherein second solvent be anhydrous methanol, dehydrated alcohol, or mixtures thereof.
Wherein, the reducing agent can be or mixtures thereof potassium borohydride, sodium borohydride.Preferably, the reducing agent is
Potassium borohydride.
Optionally, the ratio between mole of the pyridiniujm and the reducing agent is 1.0:1.0~4.0, reaction temperature
It is -10~-5 DEG C, the reaction time is 3~6h.
Further, the step S2 can also include:
Step S22 is evaporated, is extracted, is dried, is evaporated again after the completion of reaction, the N- benzyl-refined
Tetrahydropyridines.
In the following, by specific embodiment, present invention be described in more detail.
The preparation of 1 compound II-1 of embodiment
Shown in the structural formula of compound II-1 such as following formula (3).
3.2g pyridine is added in 25mL acetone, 8.30g benzyl bromine is added, is warming up to 60 DEG C of back flow reactions after 4 hours, puts
To ice-water bath, be added 13mL petroleum ether and stirring 20 minutes, filter, dry 8.6g yellow solid compound II -1, yield are
85.1%.
Reaction product is subjected to nuclear magnetic resonance experiment and confirms product structure, data are as follows:
1H NMR(500MHz,CDCl3) δ 9.57 (d, J=5.8Hz, 2H), 8.42 (t, J=7.8Hz, 1H), 8.02 (t, J
=7.1Hz, 2H), 7.68-7.66 (m, 2H), 7.32-7.31 (m, 3H), 6.28 (s, 2H).Testing result and literature value coincide.
The preparation of 2 compound II-2 of embodiment
Shown in the structural formula of compound II-2 such as following formula (4).
2g 4- picoline is added in 25mL acetone, 4.41g benzyl bromine is added, it is small to be warming up to 60 DEG C of back flow reactions 17.5
Shi Hou is put to ice-water bath, is added 13mL petroleum ether and stirring 20 minutes, filters, dry to obtain 5.1g compound as white solid II -2,
Yield is 90.0%.
Reaction product is subjected to nuclear magnetic resonance experiment and confirms product structure, data are as follows:
1H NMR(500MHz,CDCl3) δ 9.42 (d, J=6.2Hz, 2H), 7.75 (d, J=6.2Hz, 2H), 7.67-7.66
(m,2H),7.35–7.34(m,3H),6.23(s,2H),2.57(s,3H).Testing result and literature value coincide.
The preparation of 3 compound II-3 of embodiment
Shown in the structural formula of compound II-3 such as following formula (5).
0.9g 4- (4- nitrobenzophenone) pyridine is added in 10mL acetone, 0.92g benzyl bromine is added, is warming up to 60 DEG C of reflux
After reaction 19.5 hours, puts to ice-water bath, be added 5mL petroleum ether and stirring 20 minutes, filter, dry to obtain 1.5g yellow solid
Close object II -3, yield 90.0%.
Reaction product is subjected to nuclear magnetic resonance experiment and confirms product structure, data are as follows:
1H NMR(500MHz,CDCl3) δ 9.62 (d, J=6.8Hz, 2H), 8.37 (d, J=8.8Hz, 2H), 8.29 (d, J
=6.8Hz, 2H), 7.96 (d, J=8.8Hz, 2H), 7.69-7.67 (m, 2H), 7.39-7.37 (m, 3H), 6.33 (s, 2H)
Testing result and literature value coincide.
The preparation of 4 compound II-4 of embodiment
Shown in the structural formula of compound II-4 such as following formula (6).
1.6g 4- (3- nitrobenzophenone) pyridine is added in 20mL acetone, 1.64g benzyl bromine is added, is warming up to 60 DEG C of reflux
After reaction 16.5 hours, puts to ice-water bath, be added 10mL petroleum ether and stirring 20 minutes, filter, dry to obtain 2.5g yellow solid
Close object II -4, yield 84.2%.
Reaction product is subjected to nuclear magnetic resonance experiment and confirms product structure, data are as follows:
1H NMR (500MHz, DMSO) δ 9.36 (d, J=6.8Hz, 2H), 8.83 (s, 1H), 8.69 (d, J=6.8Hz,
2H), 8.50-8.47 (m, 2H), 7.94 (t, J=8.0Hz, 1H), 7.61-7.59 (m, 2H), 7.48-7.44 (m, 3H), 5.91
(s, 2H) testing result and literature value coincide.
The preparation of 5 compound II-5 of embodiment
Shown in the structural formula of compound II-5 such as following formula (7).
0.9g 4- (4- cyano-phenyl) pyridine is added in 10mL acetone, 1.03g benzyl bromine is added, is warming up to 60 DEG C of reflux
After reaction 6 hours, puts to ice-water bath, be added 5mL petroleum ether and stirring 20 minutes, filter, dry to obtain 1.5g light yellow solid chemical combination
Object II -5, yield 85.7%.
Reaction product is subjected to nuclear magnetic resonance experiment and confirms product structure, data are as follows:
1H NMR(500MHz,CDCl3) δ 9.55 (d, J=6.9Hz, 2H), 8.24 (d, J=6.9Hz, 2H), 7.88 (d, J
=8.5Hz, 2H), 7.81 (d, J=8.5Hz, 2H), 7.66-7.64 (m, 2H), 7.36-7.35 (m, 3H), 6.26 (s, 2H)
Testing result and literature value coincide.
The preparation of 6 compound III-1 of embodiment
Using the above-mentioned compound II-1 being prepared come preparation structure formula such as following formula (8) compound represented III-
1。
1.0g compound ii -1 is added in 10mL anhydrous methanol, temperature is down to -5~-10 DEG C, is slowly added to 0.65g boron
Hydrofining controls temperature at -5 DEG C or so, and after reaction 5 hours, solvent evaporated, 10mL methylene chloride is extracted, organic layer washing two
Secondary, organic phase anhydrous sodium sulfate is dry, is evaporated, obtains 0.64g pale yellowish oil liquid compound III -1, yield 92.8%.?
To sample be denoted as III -1a.
Reaction product is subjected to nuclear magnetic resonance experiment and confirms product structure, data are as follows:
1H NMR(500MHz,CDCl3)δ7.39–7.28(m,5H),5.79–5.76(m,1H),5.70–5.67(m, 1H),
3.61 (s, 2H), 3.00 (br, 2H), 2.60-2.58 (m, 2H), 2.19 (br, 2H) testing results and literature value coincide.Implement
The preparation of 7 compound III-1 of example
In addition to reducing agent is become 0.46g sodium borohydride from 0.65g potassium borohydride, with side same as above-described embodiment 7
Method prepare compound III-1, yield 82.3%.Sample is denoted as III-1b.
Reaction product is subjected to nuclear magnetic resonance experiment and confirms product structure, data are as follows:
1H NMR(500MHz,CDCl3)δ7.39–7.28(m,5H),5.79–5.76(m,1H),5.70–5.67(m, 1H),
3.61 (s, 2H), 3.00 (br, 2H), 2.60-2.58 (m, 2H), 2.19 (br, 2H) testing results and literature value coincide.Implement
The preparation of 8 compound III-2 of example
Using the above-mentioned compound II-2 being prepared come preparation structure formula such as following formula (9) compound represented III-
2。
2.0g compound ii -2 is added in 20mL anhydrous methanol, temperature is down to -5~-10 DEG C, is slowly added to 1.23g boron
Hydrofining controls temperature at -5 DEG C or so, and after reaction 6 hours, solvent evaporated, 20mL methylene chloride is extracted, organic layer washing two
Secondary, organic phase anhydrous sodium sulfate is dry, is evaporated, obtains 1.28g brown oil liquid compound III-2, yield 90.1%.Sample
It is denoted as III-2a.
Reaction product is subjected to nuclear magnetic resonance experiment and confirms product structure, data are as follows:
1H NMR(500MHz,CDCl3)δ7.38–7.28(m,5H),5.39–5.38(m,1H),3.59(s, 2H),2.95
(br, 2H), 2.57 (t, J=5.8Hz, 2H), 2.09 (br, 2H), 1.70 (s, 3H) testing results and literature value coincide.
The preparation of 9 compound III-2 of embodiment
Other than reducing agent is replaced with 0.56g sodium borohydride from 1.23g potassium borohydride, with 8 phase of above-described embodiment
With and method prepare compound III-2.Yield is 76.1%.Sample is denoted as III-2b.
Reaction product is subjected to nuclear magnetic resonance experiment and confirms product structure, data are as follows:
1H NMR(500MHz,CDCl3)δ7.38–7.28(m,5H),5.39–5.38(m,1H),3.59(s, 2H),2.95
(br, 2H), 2.57 (t, J=5.8Hz, 2H), 2.09 (br, 2H), 1.70 (s, 3H) testing results and literature value coincide.
The preparation of 10 compound III-3 of embodiment
Using the above-mentioned compound II-3 being prepared come preparation structure formula such as following formula (10) compound represented III-
3。
1.5g compound ii -3 is added in 20mL anhydrous methanol, temperature is down to -5~-10 DEG C, is slowly added to 0.65g boron
Hydrofining controls temperature at -5 DEG C or so, and after reaction 4 hours, solvent evaporated, 15mL methylene chloride is extracted, organic layer washing two
Secondary, organic phase anhydrous sodium sulfate is dry, is evaporated, obtains 1.05g yellow solid compound III -3, yield 88.2%.Sample is denoted as
III-3a。
Reaction product is subjected to nuclear magnetic resonance experiment and confirms product structure, data are as follows:
1H NMR(500MHz,CDCl3)δ8.18–8.15(m,2H),7.53–7.50(m,2H),7.38 –7.28(m,5H),
6.28-6.27 (m, 1H), 3.66 (s, 2H), 3.23-3.21 (m, 2H), 2.75 (t, J=5.7Hz, 2H), 2.59-2.57 (m,
2H) testing result and literature value coincide.
The preparation of 11 compound III-3 of embodiment
Other than reducing agent is replaced with 0.46g sodium borohydride from 0.65g potassium borohydride, with above-described embodiment 10
Identical and method prepare compound III-3.Yield is 68.9%.Sample is denoted as III-3b.
Reaction product is subjected to nuclear magnetic resonance experiment and confirms product structure, data are as follows:
1H NMR(500MHz,CDCl3)δ8.18–8.15(m,2H),7.53–7.50(m,2H),7.38 –7.28(m,5H),
6.28-6.27 (m, 1H), 3.66 (s, 2H), 3.23-3.21 (m, 2H), 2.75 (t, J=5.7Hz, 2H), 2.59-2.57 (m,
2H) testing result and literature value coincide.
The preparation of 12 compound III-4 of embodiment
Using the above-mentioned compound II-4 being prepared come preparation structure formula such as following formula (11) compound represented III-
4。
1.0g compound ii -4 is added in 10mL anhydrous methanol, temperature is down to -5~-10 DEG C, is slowly added to 0.44g boron
Hydrofining controls temperature at -5 DEG C or so, and after reaction 4.5 hours, solvent evaporated, 10mL methylene chloride is extracted, organic layer washing
Twice, organic phase anhydrous sodium sulfate is dry, is evaporated, obtains 0.70g faint yellow solid compound III -4, yield 88.6%.Sample
It is denoted as III-4a.
Reaction product is subjected to nuclear magnetic resonance experiment and confirms product structure, data are as follows:
1H NMR(500MHz,CDCl3) δ 8.23 (t, J=1.9Hz, 1H), 8.08 (dd, J=8.1,1.5Hz, 1H),
7.70 (d, J=7.9Hz, 1H), 7.47 (t, J=8.0Hz, 1H), 7.39-7.27 (m, 5H), 6.23-6.22 (m, 1H), 3.66
(s, 2H), 3.22-3.20 (m, 2H), 2.75 (t, J=5.7Hz, 2H), 2.60-2.58 (m, 2H) testing results and literature value
It coincide.
The preparation of 13 compound III-4 of embodiment
Other than reducing agent is replaced with 0.31g sodium borohydride from 0.44g potassium borohydride, with above-described embodiment 12
Identical and method prepare compound III-4.Yield is 70.9%.Sample is denoted as III-4b.
Reaction product is subjected to nuclear magnetic resonance experiment and confirms product structure, data are as follows:
1H NMR(500MHz,CDCl3) δ 8.23 (t, J=1.9Hz, 1H), 8.08 (dd, J=8.1,1.5 Hz, 1H),
7.70 (d, J=7.9Hz, 1H), 7.47 (t, J=8.0Hz, 1H), 7.39-7.27 (m, 5H), 6.23-6.22 (m, 1H), 3.66
(s, 2H), 3.22-3.20 (m, 2H), 2.75 (t, J=5.7Hz, 2H), 2.60-2.58 (m, 2H) testing results and literature value
It coincide.
The preparation of 14 compound III-5 of embodiment
Using the above-mentioned compound II-5 being prepared come preparation structure formula such as following formula (12) compound represented III-
5。
By 1.0g compound ii-5It is added in 10mL anhydrous methanol, temperature is down to -5~-10 DEG C, is slowly added to 0.46g boron
Hydrofining controls temperature at -5 DEG C or so, and after reaction 4.5 hours, solvent evaporated, 10mL methylene chloride is extracted, organic layer washing
Twice, organic phase anhydrous sodium sulfate is dry, is evaporated, obtains 0.70g faint yellow solid compound III -5, yield 89.7%.Sample
It is denoted as III-5a.
Reaction product is subjected to nuclear magnetic resonance experiment and confirms product structure, data are as follows:
1H NMR(500MHz,CDCl3)δ7.60–7.58(m,2H),7.47–7.45(m,2H),7.38 –7.27(m,5H),
6.22-6.20 (m, 1H), 3.65 (s, 2H), 3.21-3.20 (m, 2H), 2.73 (t, J=5.7Hz, 2H), 2.56-2.53 (m,
2H) testing result and literature value coincide.
The preparation of 15 compound III-5 of embodiment
Other than reducing agent is replaced with 0.32g sodium borohydride from 0.46g potassium borohydride, with above-described embodiment 14
Identical and method prepare compound III-5.Yield is 67.4%.Sample is denoted as III-5b.
Reaction product is subjected to nuclear magnetic resonance experiment and confirms product structure, data are as follows:
1H NMR(500MHz,CDCl3)δ7.60–7.58(m,2H),7.47–7.45(m,2H),7.38 –7.27(m,5H),
6.22-6.20 (m, 1H), 3.65 (s, 2H), 3.21-3.20 (m, 2H), 2.73 (t, J=5.7Hz, 2H), 2.56-2.53 (m,
2H).
Testing result and literature value coincide.
Above-described embodiment 6 to embodiment 15 is compared, result is as shown in table 1 below.
The yield (%) that table 1 is obtained using different reducing agent KBH4 and NaBH4
By 1 result of table, it is found that N- of the present invention benzyl-tetrahydropyridine preparation method has, synthetic route is brief, operates
The advantage easy, by-product is few, yield is high, especially in the case where selecting potassium borohydride as reducing agent, yield is higher.
The above is a preferred embodiment of the present invention, it is noted that for those skilled in the art
For, without departing from the principles of the present invention, it can also make several improvements and retouch, these improvements and modifications
Also it should be regarded as protection scope of the present invention.
Claims (10)
1. a kind of preparation method of N- benzyl-tetrahydropyridines, which comprises the steps of:
Benzyl bromine is added in step S1 in pyridine compounds and their, and nucleophilic substitution occurs, obtains pyridiniujm；
Step S2 makes the pyridiniujm and reducing agent that reduction reaction occur, obtains the N- benzyl-tetrahydropyridine class chemical combination
Object.
2. preparation method according to claim 1, which is characterized in that the step S1 includes:
Step S11, the pyridine compounds and their is dispersed in the first organic solvent, the benzyl bromine is added wherein parent occurs
Core substitution reaction, obtains the pyridiniujm, and first organic solvent is acetone, tetrahydrofuran, acetonitrile, toluene or it is mixed
Close object.
3. preparation method according to claim 2, which is characterized in that the step S1 further include:
Step S12 carries out cooling after the completion of reaction, filters and dry to refine to the pyridiniujm.
4. preparation method according to claim 2, which is characterized in that mole of the pyridine compounds and their and the benzyl bromine
Than for 1.0:1.0~1.5, reaction temperature is 20~90 DEG C, the reaction time is 4~20h.
5. preparation method according to claim 1, which is characterized in that the step S2 includes:
In a second organic solvent by pyridiniujm dispersion, and the reducing agent is added wherein to occur also in step S21
Original reaction, wherein second solvent be anhydrous methanol, dehydrated alcohol, or mixtures thereof.
6. preparation method according to claim 5, which is characterized in that the step S2 further include:
Step S22 is evaporated, is extracted, is dried, is evaporated again after the completion of reaction, the N- benzyl-tetrahydro refined
Pyridine compounds and their.
7. preparation method according to claim 6, which is characterized in that the reducing agent be potassium borohydride, sodium borohydride or
Its mixture.
8. preparation method according to claim 7, which is characterized in that the reducing agent is potassium borohydride.
9. preparation method according to claim 6, which is characterized in that the mole of the pyridiniujm and the reducing agent
The ratio between be 1.0:1.0~4.0, reaction temperature be -10~-5 DEG C, the reaction time be 3~6h.
10. N- benzyl-tetrahydropyridines that preparation method according to any one of claims 1 to 9 is prepared.
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