CN110128500A - Prepare α-amide groups amide substance Ugi mixed solvent method - Google Patents
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- CN110128500A CN110128500A CN201910355883.0A CN201910355883A CN110128500A CN 110128500 A CN110128500 A CN 110128500A CN 201910355883 A CN201910355883 A CN 201910355883A CN 110128500 A CN110128500 A CN 110128500A
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- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
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- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
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Abstract
α-amide groups amide substance Ugi mixed solvent method is prepared the invention discloses a kind of, comprising the following steps: under inert gas shielding, is first at room temperature stirred isobutylaldehyde, 3-Aminotrifluorotoluene in the mixed solvent；Then isocyano acid B ester is added dropwise after glacial acetic acid uniform stirring being added under condition of ice bath, removes ice bath after being added dropwise, is stirred to react 8~12h under conditions of room temperature, inert gas shielding；Resulting reaction solution is concentrated, resulting crude product is post-treated, obtains N- acetyl group-N- [3- (trifluoromethyl) phenyl] valyl base glycine ethyl ester.This method uses mixed solvent, can increase reaction conversion ratio and yield.
Description
Technical field
The present invention relates to a kind of synthetic method of organic compound, in particular to a kind of α-amide groups amide substance ---
Ugi multicomponent synthetic method (the Ugi mixed solvent of N- acetyl group-N- [3- (trifluoromethyl) phenyl] valyl base glycine ethyl ester
Synthetic method).
Background technique
N- acetyl group-N- [3- (trifluoromethyl) phenyl] valyl base glycine ethyl ester, structural formula are as follows:
It belongs to α-amide groups amide substance, and historically it is used in the research such as drug, cosmetics, biochemistry
Field, especially as protease inhibitors with anti-cell aging in terms of, have effects that significantly study.
α-amide groups amide substance is a kind of important organic synthesis skeleton, and conventional multi-route synthetic method is more multiple
It is miscellaneous, it is mostly used some multiple groups point-score reactions relatively now to establish the library of molecules of this substance, common is that Ugi reacts.
In the synthesis of N- acetyl group-N- [3- (trifluoromethyl) phenyl] valyl base glycine ethyl ester, according to mechanism, first have to
3-Aminotrifluorotoluene and isobutyl aldehyde reaction are generated into imines, then protonated by carboxylic acid, finally is merged to be formed with isonitrile
After nitrilium, is reset in conjunction with carboxylate radical, obtain target molecule.
In existing record, while teaching its effect, it is made frequently with the mono- solvent synthetic method of Ugi
It is standby, it is carried out using single solvent methanol, specially (EP1275372A1):
0.63ml isobutylaldehyde and 1ml 3-Aminotrifluorotoluene (1.15 molar equivalent) are mixed in 15ml methanol under stiring
It closes, reacts mixture at 20 DEG C 15 minutes, 0.46ml acetic acid (1.15 molar equivalent) then is added, and react 10 at 20 DEG C
Minute.Then the isocyanide yl acetate (1 molar equivalent) of 0.8ml 95% is added and carries out reaction 48 hours at 20 DEG C.Place
When reason, reaction medium is concentrated in Rotary Evaporators, and residue is purified on a silica gel column, eluant, eluent is heptane/acetic acid
Ethyl ester=3:7 (v/v)；Rf=0.5；Yield has 91%.
Summary of the invention
α-amide groups amide substance Ugi mixed solvent method is prepared the technical problem to be solved by the present invention is to provide a kind of,
That is, providing a kind of Ugi mixed solvent synthesis of N- acetyl group-N- [3- (trifluoromethyl) phenyl] valyl base glycine ethyl ester
Method, this method use mixed solvent, to increase reaction conversion ratio and yield.
In order to solve the above technical problem, the present invention provides it is a kind of prepare α-amide groups amide substance Ugi mixing it is molten
Agent method, comprising the following steps:
1), under inert gas (such as nitrogen) protection, first at room temperature by isobutylaldehyde, 3-Aminotrifluorotoluene in mixing
(1 ± 0.2) h is stirred in solvent, glacial acetic acid uniform stirring is then added under the conditions of ice bath (0~5 DEG C), and (mixing time is about
(being slowly added dropwise) isocyano acid B ester (or, mixed liquor of isocyano acid B ester) 5min) is added dropwise afterwards, is controlled during being added dropwise
Ice bath is removed after being added dropwise in temperature≤5 DEG C of system, is stirred to react 8~12h under conditions of room temperature, inert gas shielding；
Isobutylaldehyde: m-trifluoromethyl benzene: glacial acetic acid: isocyano acid B ester=1:(1 ± 0.02): (1 ± 0.02): (1 ±
0.02) molar ratio；
Note: removing ice bath, warms naturally to room temperature；Reaction monitoring can be carried out by HPLC；Above-mentioned entire reaction process is equal
It needs to be protected with inert gas (such as nitrogen)；
2), by the resulting reaction solution concentration (concentrated by rotary evaporation, to remove mixed solvent) of step 1), resulting crude product is (deep
Brown oil) post-treated (referring mainly to column chromatography), obtain N- acetyl group-N- [3- (trifluoromethyl) phenyl] valyl base glycine
Ethyl ester.
As the improvement for preparing α-amide groups amide substance Ugi mixed solvent method of the invention:
Mixed solvent is by polar aprotic solvent: polar non-solute=5:1~3:1 volume ratio (v/v) mixes.
As the further improvement for preparing α-amide groups amide substance Ugi mixed solvent method of the invention:
The polar aprotic solvent is lower alcohol, and the lower alcohol includes methanol, ethyl alcohol；
The polar non-solute is anhydrous acetonitrile.
As the further improvement for preparing α-amide groups amide substance Ugi mixed solvent method of the invention:
In the step 1), the liquid-to-solid ratio of mixed solvent and isocyano acid B ester is (10 ± 2) ml/1g.
As the further improvement for preparing α-amide groups amide substance Ugi mixed solvent method of the invention:
Mixed solvent is by methanol: acetonitrile=3~4:1 volume ratio (v/v) mixes；Mixed solvent and isocyanide guanidine-acetic acid
The liquid-to-solid ratio of ethyl ester is 10ml/1g.
As the further improvement for preparing α-amide groups amide substance Ugi mixed solvent method of the invention:
The mixed of isocyano acid B ester is formed in the step 1), after first mixing isocyano acid B ester with mixed solvent
Close liquid；In mixed liquor, the volume content of isocyano acid B ester is 40~60%；
The mixed liquor of isocyano acid B ester is added dropwise and (is slowly added dropwise) again；Temperature≤5 DEG C of control system during dropwise addition.
As the further improvement for preparing α-amide groups amide substance Ugi mixed solvent method of the invention: step 2)
Post-processing are as follows:
By crude product after ethyl acetate dissolution, washing dry (sodium sulphate is dry), silica gel mixed sample is added, after column purification,
Obtain N- acetyl group-N- [3- (trifluoromethyl) phenyl] valyl base glycine ethyl ester (for white-yellowish solid, purity >=98%
Sterling).
As the further improvement for preparing α-amide groups amide substance Ugi mixed solvent method of the invention: the step
In rapid post-processing 2):
The solid-liquid ratio of crude product and ethyl acetate is 1g/ (10 ± 2) ml；
To be washed using water or NaCL aqueous solution, washing times are 2~3 times for the washing, every time when washing water or
The dosage of NaCL aqueous solution is (0.2 ± 0.1) volume times of ethyl acetate.
Note: liquid separation each time after washing, then carry out subsequent washing.
As the further improvement for preparing α-amide groups amide substance Ugi mixed solvent method of the invention: the step
In rapid post-processing 2):
Silica gel is the silica gel of 200-300 mesh, the silica gel: crude product=(1.2 ± 0.1): 1 mass ratio, when column purification
Eluent is petroleum ether: ethyl acetate=5:1 volume ratio (v/v) mixed liquor.
Note: after solvent in silica gel (ethyl acetate of dissolution crude product) is drained, then column purification is carried out.
Synthetic method of the invention is divided into former and later two stage (glacial acetic acid and isocyano acid B esters at 25 DEG C of Yu Changwen
It is added under condition of ice bath between above-mentioned 2 stages) one pot reaction is carried out, total reaction time is about 9~13h, most rear pillar
Purifying obtains N- acetyl group-N- [3- (trifluoromethyl) phenyl] valyl base glycine ethyl ester of high yield；Yield of the invention
It can achieve 98~99%.
Reaction equation of the invention is as follows:
The present invention is used to be existed in mixed solvent (being made of a kind of polar aprotic solvent and a kind of polar non-solute)
Under conditions of, the reaction of tetra- component of Ugi is completed, has achieved the purpose that improve conversion ratio and yield, operation is simple, solvent
It is low in cost.
In conclusion N- acetyl group-N- [3- (trifluoromethyl) phenyl] valyl base glycine ethyl ester Ugi of the invention is mixed
The preparation of bonding solvent method, has following technical advantage:
1, it feeds intake relative to conventional single Solvent method and routine, the reaction deadline is shorter, conversion ratio and high income；Section
Synthesis cost is saved.
2, used mixed solvent is common cheap less toxic organic solvent, at low cost, and it is small to obtain difficulty.
Specific embodiment
In following case: room temperature generally refers to 20~25 DEG C；The revolving speed of stirring is about 600~800rpm.
Nitrogen environment can be provided by threeway and the displacement of nitrogen ball, this is routine techniques.
Embodiment 1, it is a kind of prepare α-amide groups amide substance Ugi mixed solvent method, successively follow the steps below:
One, it reacts:
1) magnetic rotor, at room temperature, is added in 250ml three-necked flask, is equipped with thermometer, and mixed solvent (first is added
Alcohol: acetonitrile=3:1, v/v) 95ml；
Under nitrogen protection, 6.06g (83.98mmol, 1.0eq) isobutylaldehyde, 13.53g (83.98mmol, 1.0eq) is added
Mamino-trifluoromethyl benzene stirs 1h at room temperature；
2) it, continues under nitrogen protection, the gains of step 1) is set among ice bath, stir, until thermometer registration
It when being down to 0~5 DEG C, is added glacial acetic acid 5.04g (83.98mmol, 1.0eq), stirs 5min, be then slowly added dropwise with dropping funel
Isocyano acid B ester 9.50g (83.98mmol, 1.0eq) controls speed during being added dropwise, thus temperature≤5 of control system
DEG C, time for adding is about 15 minutes；After being added dropwise, ice bath is removed, system is made to warm naturally to room temperature, is stirred to react 12h；This
When, HPLC monitoring reaction terminates.
Two, by the resulting reaction solution concentrated by rotary evaporation of step 1 (pressure, 40 DEG C of the temperature of 0.02mpa), to remove mixed
Bonding solvent obtains the crude product 35.0g of dark-brown oily；
Above-mentioned crude product is dissolved in ethyl acetate 388ml, is washed using saturation NaCl aqueous solution, washing 3 times, often
When secondary washing, the dosage of saturation NaCl aqueous solution is 78ml (liquid separation each time after washing, then carry out subsequent washing)；Then it uses
Sodium sulphate dries, filters the 200-300 mesh silica gel that 42.0g (1.2 crude product qualities times) are added in rear resulting filtrate, mixes sample and drains
(that is, contained ethyl acetate is removed using concentrated by rotary evaporation (pressure of 0.02mpa, 40 DEG C of temperature)), upper column purification；
Using petroleum ether: the mixed liquor of ethyl acetate=5:1 (v/v) is eluted to as eluant, eluent and meets TLC expansion elution
When liquid no longer shows product fluorescence under 254nm ultraviolet wavelength, stop elution, the dosage of eluant, eluent is about 1200ml at this time；
All elution gains are collected, it is solid to obtain 31.9g yellow-white after concentration (pressure of 0.02mpa, 40 DEG C of temperature)
Body ----N- acetyl group-N- [3- (trifluoromethyl) phenyl] valyl base glycine ethyl ester (purity >=98%), yield 98.0%.
Embodiment 2, it is a kind of prepare α-amide groups amide substance Ugi mixed solvent method, successively follow the steps below:
One, it reacts:
1) magnetic rotor, at room temperature, is added in 250ml three-necked flask, is equipped with thermometer, and mixed solvent (second is added
Alcohol: acetonitrile=5:1) 40ml；
Under nitrogen protection, it is added between 3.19g (44.2mmol, 1.0eq) isobutylaldehyde, 7.12g (44.2mmol, 1.0eq)
5 amido benzotrifluoride stirs 1h at room temperature；
2) it, continues under nitrogen protection, the gains of step 1) is set among ice bath, stir, until thermometer registration
It when being down to 0~5 DEG C, is added glacial acetic acid 2.65g (44.2mmol, 1.0eq), stirs 5min, be then slowly added dropwise with dropping funel
(the 10ml solution is by isocyano acid B ester by solution 10ml containing isocyano acid B ester 5.00g (44.2mmol, 1.0eq)
44.2mmol (4.83ml) and as surplus mixed solvent form), be added dropwise during control speed, thus the temperature of control system
≤ 5 DEG C of degree, time for adding is about 15 minutes；After being added dropwise, ice bath is removed, system is made to warm naturally to room temperature, is stirred to react
8h；At this point, HPLC monitoring reaction terminates.
Two, the resulting reaction solution concentrated by rotary evaporation of step 1 is obtained into the crude product of dark-brown oily to remove mixed solvent
18.1g；
Above-mentioned crude product is dissolved in ethyl acetate 200ml, is washed using saturation NaCL aqueous solution, washing 3 times, often
When secondary washing, the dosage of saturation NaCL aqueous solution is 40ml (liquid separation each time after washing, then carry out subsequent washing)；Then it uses
Sodium sulphate dries, filters the 200-300 mesh silica gel that 21.7g (1.2 crude product qualities times) are added in rear resulting filtrate, mixes sample and drains,
Upper column purification；
Using petroleum ether: the mixed liquor of ethyl acetate=5:1 (v/v) is eluted to as eluant, eluent and meets TLC expansion elution
Liquid stops elution when no longer showing product fluorescence under 254nm ultraviolet wavelength, and the dosage of eluant, eluent is about 600ml at this time；；
All elution gains are collected, 17.0g white-yellowish solid is concentrated to give ----N- acetyl group-N- [3- (fluoroform
Base) phenyl] valyl base glycine ethyl ester (purity >=98%), yield 99%.
Embodiment 3, by 2 step 12 of embodiment) in " be added dropwise containing isocyano acid B ester 5.00g (44.2mmol,
Solution 10ml " 1.0eq) is changed to " being added dropwise isocyano acid B ester 5.00g (44.2mmol, 1.0eq) "；Remaining is equal to implementation
Example 2；
Final resulting yield is 97%.
Embodiment 4, it is a kind of prepare α-amide groups amide substance Ugi mixed solvent method, successively follow the steps below:
One, it reacts:
1) magnetic rotor, at room temperature, is added in 100ml three-necked flask, is equipped with thermometer, and mixed solvent (first is added
Alcohol: acetonitrile=4:1) 20ml；
Under nitrogen protection, 1.28g (17.68mmol, 1.0eq) isobutylaldehyde, 2.85g (17.68mmol, 1.0eq) is added
Mamino-trifluoromethyl benzene stirs 1h at room temperature；
2) it, continues under nitrogen protection, the gains of step 1) is set among ice bath, stir, until thermometer registration
It when being down to 0~5 DEG C, is added glacial acetic acid 1.06g (17.68mmol, 1.0eq), stirs 5min, be then slowly added dropwise with dropping funel
Isocyano acid B ester 2.00g (17.68mmol, 1.0eq) controls speed during being added dropwise, thus temperature≤5 of control system
DEG C, time for adding is about 10 minutes；After being added dropwise, ice bath is removed, system is made to warm naturally to room temperature, is stirred to react 10h；This
When, HPLC monitoring reaction terminates.
Two, the resulting reaction solution concentrated by rotary evaporation of step 1 is obtained into the crude product of dark-brown oily to remove mixed solvent
7.3g；
Above-mentioned crude product is dissolved in ethyl acetate 80ml, is washed using saturation NaCL aqueous solution, washing 3 times, often
When secondary washing, the dosage of saturation NaCL aqueous solution is 16ml (liquid separation each time after washing, then carry out subsequent washing)；Then it uses
Sodium sulphate dries, filters the 200-300 mesh silica gel that 8.8g (1.2 crude product qualities times) are added in rear resulting filtrate, mixes sample and drains, on
Column purification；
Using petroleum ether: the mixed liquor of ethyl acetate=5:1 (v/v) is eluted to as eluant, eluent and meets TLC expansion elution
Liquid stops elution when no longer showing product fluorescence under 254nm ultraviolet wavelength, and the dosage of eluant, eluent is about 250ml at this time；
All elution gains are collected, is concentrated, obtains 6.75g white-yellowish solid ----N- acetyl group-N- [3- (fluoroform
Base) phenyl] valyl base glycine ethyl ester (purity >=98%), yield 98.4%.
Mamino-trifluoromethyl benzene, glacial acetic acid in 4 step 1 of embodiment by 1.0eq is changed to 1.15eq by comparative example 1
(that is, 20.332mmol is changed to by 17.68mmol)；Remaining is equal to embodiment 4；
Final resulting product ----N- acetyl group-N- [3- (trifluoromethyl) phenyl] valyl base glycine ethyl ester yield
It is 91.4%.
Comparative example 2, by 4 step 11 of embodiment) in mixed solvent (methanol: acetonitrile=4:1) be described in table 1 below instead
Solvent, dosage is constant, is still 20ml；Remaining is equal to embodiment 4；Final resulting product yield is described in table 1 below.
Table 1
Comparative example 3, cancel 4 step 12 of embodiment) in " ice bath " setting；That is, by step 1 2) it is changed to are as follows:
2), continue under nitrogen protection, into the gains of step 1) be added glacial acetic acid 1.06g (17.68mmol,
1.0eq), 5min is stirred, is then slowly added dropwise isocyano acid B ester 2.00g (17.68mmol, 1.0eq) with dropping funel, is dripped
With embodiment 4 between added-time, it is stirred to react after being added dropwise until HPLC monitoring reaction terminates；Reaction time is about 11h.
Final resulting product yield is 94.6%.
Finally, it should also be noted that it is listed above be only separate embodiment of the invention.Obviously, the present invention is unlimited
In above embodiments, acceptable there are many deformations.Those skilled in the art can directly lead from present disclosure
Out or all deformations for associating, it is considered as protection scope of the present invention.
Claims (9)
1. α-amide groups amide substance Ugi mixed solvent method is prepared, it is characterized in that the following steps are included:
1), under inert gas shielding, first at room temperature by isobutylaldehyde, 3-Aminotrifluorotoluene in the mixed solvent stir (1 ±
0.2) isocyano acid B ester, control volume during dropwise addition is added dropwise after glacial acetic acid uniform stirring then is added under condition of ice bath in h
Ice bath is removed after being added dropwise in temperature≤5 DEG C of system, is stirred to react 8~12h under conditions of room temperature, inert gas shielding；
Isobutylaldehyde: m-trifluoromethyl benzene: glacial acetic acid: isocyano acid B ester=1:(1 ± 0.02): (1 ± 0.02): (1 ±
0.02) molar ratio；
2), the resulting reaction solution of step 1) is concentrated, resulting crude product is post-treated, obtains N- acetyl group-N- [3- (trifluoromethyl)
Phenyl] valyl base glycine ethyl ester.
2. according to claim 1 prepare α-amide groups amide substance Ugi mixed solvent method, it is characterized in that:
Mixed solvent is by polar aprotic solvent: polar non-solute=5:1~3:1 volume ratio mixes.
3. according to claim 2 prepare α-amide groups amide substance Ugi mixed solvent method, it is characterized in that:
The polar aprotic solvent is lower alcohol, and the lower alcohol includes methanol, ethyl alcohol；
The polar non-solute is anhydrous acetonitrile.
4. according to claim 3 prepare α-amide groups amide substance Ugi mixed solvent method, it is characterized in that:
In the step 1), the liquid-to-solid ratio of mixed solvent and isocyano acid B ester is (10 ± 2) ml/1g.
5. according to claim 4 prepare α-amide groups amide substance Ugi mixed solvent method, it is characterized in that:
Mixed solvent is by methanol: acetonitrile=3~4:1 volume ratio mixes；The liquid of mixed solvent and isocyano acid B ester
Material is than being 10ml/1g.
6. any according to claim 1~5 described prepare α-amide groups amide substance Ugi mixed solvent method, feature
It is:
In the step 1), the mixing of isocyano acid B ester is formed after first mixing isocyano acid B ester with mixed solvent
Liquid；In mixed liquor, the volume content of isocyano acid B ester is 40~60%；
The mixed liquor of isocyano acid B ester is added dropwise again；Temperature≤5 DEG C of control system during dropwise addition.
7. any according to claim 1~6 described prepare α-amide groups amide substance Ugi mixed solvent method, feature
It is the post-processing of the step 2) are as follows:
Crude product is dry after ethyl acetate dissolution, washing, silica gel mixed sample is added and obtains N- acetyl group-N- after column purification
[3- (trifluoromethyl) phenyl] valyl base glycine ethyl ester.
8. according to claim 7 prepare α-amide groups amide substance Ugi mixed solvent method, it is characterized in that the step
In rapid post-processing 2):
The solid-liquid ratio of crude product and ethyl acetate is 1g/ (10 ± 2) ml；
To be washed using water or NaCL aqueous solution, washing times are 2~3 times for the washing, every time water or NaCL when washing
The dosage of aqueous solution is (0.2 ± 0.1) volume times of ethyl acetate.
9. according to claim 8 prepare α-amide groups amide substance Ugi mixed solvent method, it is characterized in that the step
In rapid post-processing 2):
Silica gel is the silica gel of 200-300 mesh, the silica gel: crude product=(1.2 ± 0.1): 1 mass ratio, elution when column purification
Liquid is petroleum ether: ethyl acetate=5:1 volume ratio mixed liquor.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113999154A (en) * | 2021-06-23 | 2022-02-01 | 国药东风总医院 | Compound and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1436197A (en) * | 2000-06-08 | 2003-08-13 | 莱雅公司 | Novel compounds of N-acylamino-amide family, compositions comprising same and uses |
| CN107001412A (en) * | 2014-12-18 | 2017-08-01 | 莱雅公司 | Compound in N acyl aminoacid amides family, include their compositions and purposes |
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2019
- 2019-04-29 CN CN201910355883.0A patent/CN110128500B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1436197A (en) * | 2000-06-08 | 2003-08-13 | 莱雅公司 | Novel compounds of N-acylamino-amide family, compositions comprising same and uses |
| CN107001412A (en) * | 2014-12-18 | 2017-08-01 | 莱雅公司 | Compound in N acyl aminoacid amides family, include their compositions and purposes |
Non-Patent Citations (1)
| Title |
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| 邓兰青等: "Ugi 多组分反应一锅法合成 3-异吲哚酮-1-甲酰胺衍生物", 《应用化工》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113999154A (en) * | 2021-06-23 | 2022-02-01 | 国药东风总医院 | Compound and preparation method and application thereof |
| CN113999154B (en) * | 2021-06-23 | 2023-03-21 | 国药东风总医院 | Compound and preparation method and application thereof |
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