CN102531990B - 2-(4- OBzl-2-oxo-2,5-pyrroline-1-yl)-acetamide and synthesis and application thereof - Google Patents
2-(4- OBzl-2-oxo-2,5-pyrroline-1-yl)-acetamide and synthesis and application thereof Download PDFInfo
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- CN102531990B CN102531990B CN201110449587.0A CN201110449587A CN102531990B CN 102531990 B CN102531990 B CN 102531990B CN 201110449587 A CN201110449587 A CN 201110449587A CN 102531990 B CN102531990 B CN 102531990B
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Abstract
The invention discloses 2-(4- OBzl-2-oxo-2,5-pyrroline-1-yl)-acetamide and synthesis and application thereof. The structure of 2-(4- OBzl-2-oxo-2,5-pyrroline-1-yl)-acetamide is indicated as the formula (3), and the synthesis route is indicated as follows. 2-(4- OBzl-2-oxo-2,5-pyrroline-1-yl)-acetamide can serve as an intermediate to be used for synthesis of oxiracetam, has the advantages that synthesis steps are short, operation is simple and convenient, raw materials are cheap and easy to obtain and emission of three wastes is little, and enjoys broad industrial application prospects.
Description
(1) technical field
The present invention relates to 2-(4-benzyloxy-2-oxo-2,5-pyrroline-1-yl)-ethanamide, its synthetic method using and as the application of the key intermediate of synthesis of pyrrolidine ketone nootropics oxiracetam.
(2) background technology
Oxiracetam (Oxiracetam), chemical name is Esomeprazole, structure is as follows:
Oxiracetam is pyrrolidinone compounds nootropics, is used for the treatment of clinically the brain insufficiency that a variety of causes causes, is to think at present one of the most promising Novel intelligence developmental medicine.This medicine can act on hippocampus, pallium and striatum by highly selective, has hypermnesis, the anti-effect of forgeing.
Oxiracetam is synthetic by the exploitation first in 1974 of Italian ISF company, listing in 1987.So far the synthesis technique patent that existing many companies have applied for oxiracetam, mainly contains following two kinds of synthetic methods:
A kind of synthetic method of very early time is first synthesis of pyrrolidine, then obtain target product through steps such as reduction, replacement, ammonifications, the main problem existing is that reactions steps is many, length consuming time, total recovery is low, and atom economy type is not high, in addition, raw material is not easy to obtain and is expensive, and intermediate or product are difficult for purifying, and some technique even uses the material that toxicity is larger;
Recent application is more a kind of is first from basis, inexpensive β, the butyric acid alkyl ester or 3 that γ replaces, 4 epoxy butyric acid alkyl derivatives are starting raw material, through hydroxyl protection, cyclization, deprotection, the synthetic target product such as ammonification, or after the hydrochlorate one step to form the loop of direct and G-NH2, productive target product, in Japanese Patent JP62026267, propose directly to react to prepare target product oxiracetam with G-NH2 with 3-hydroxyl-4-halo butanoic acid derivative, but side reaction is many in this method, reaction product complicated component, after refining, can not reach the requirement that medicine uses completely, long reaction time in addition, and ultimate yield is low, can not meet the needs of commercial scale production.
To sum up, at present in synthetic route major defect be raw material more expensive be not easy to obtain and part also toxicity is large, security is low, synthetic route is long, complicated operation, purification does not reach demand of industrial production, and environmental pollution is serious.
(3) summary of the invention
The technical problem to be solved in the present invention is to provide a kind of new compound---2-(4-benzyloxy-2-oxo-2,5-pyrroline-1-yl)-ethanamide, utilize this compound to prepare the synthetic route of oxiracetam as intermediate, have advantages of that raw material is cheap and easy to get, step is short, easy and simple to handle, three waste discharge is few.
2-of the present invention (4-benzyloxy-2-oxo-2,5-pyrroline-1-yl)-ethanamide, its structure as the formula (3):
The invention provides that a kind of raw material is cheap and easy to get, step is short, easy and simple to handle, reaction yield is high, the synthetic method of good product quality, 2-(4-benzyloxy-2-oxo-2,5-pyrroline-1-yl)-ethanamide that three waste discharge is few.
The present invention adopts following technical scheme:
A kind of synthetic method of 2-(4-benzyloxy-2-oxo-2,5-pyrroline-1-yl)-ethanamide, comprises the steps:
1) take the 4-chloro methyl acetoacetate shown in formula (1) as starting raw material, 4-chloro methyl acetoacetate and phenylcarbinol in non-protonic solvent under lewis acidic catalysis back flow reaction, obtain the chloro-2-butylene of the 3-benzyloxy-4-shown in formula (2) acid methyl esters;
2) the chloro-2-butylene acid methyl esters of 3-benzyloxy-4-and glycyl amide hydrochloride carry out ring-closure reaction in polar solvent under alkaline condition, 20-200 ℃ temperature condition, fully after reaction, gained reaction solution obtains target product 2-(4-benzyloxy-2-oxo-2,5-pyrroline-1-yl)-ethanamide through separation and purification.
Synthetic route is as follows:
Step 1 of the present invention) in, it is one of following that described non-protonic solvent is selected from: hexanaphthene, benzene,toluene,xylene, ether, dimethyl sulfoxide (DMSO), dimethyl formamide, acetone, acetonitrile.Preferred non-protonic solvent is one of following: hexanaphthene, benzene, toluene, dimethylbenzene.
Step 1 of the present invention) described catalyzer is Lewis acid, as tosic acid, trifluoromethanesulfonic acid, boron trifluoride, aluminum chloride, tin tetrachloride, iron(ic) chloride, hydrochloric acid, sulfuric acid.Preferred catalyzer is one of following: tosic acid, trifluoromethanesulfonic acid, boron trifluoride, aluminum chloride, tin tetrachloride.Most preferred catalysts is tin tetrachloride.
In step 1) of the present invention, the molar ratio of described 4-chloro methyl acetoacetate and phenylcarbinol is 1:1～1.8, is preferably 1:1～1.4.
In the present invention, the described lewis acidic quality that adds is 1～8% of 4-chloro methyl acetoacetate quality, is preferably 1～5%.
Step 1 of the present invention) described reaction times, preferably the time was 3-10h generally at 2-20h.
After described in step 1) of the present invention, reaction proceeds to completely, gained reaction solution obtains the chloro-2-butylene acid of 3-benzyloxy-4-methyl esters crude product after steaming and desolventizing, this crude product can be directly used in next step reaction without refining, so not only simplify experimental implementation, and avoided separation losses, productive rate is increased.
Step 2 of the present invention) described polar solvent is preferably alcohols, as methyl alcohol, ethanol, Virahol, propyl carbinol or the trimethyl carbinol.
Step 2 of the present invention) can be by adding alkaline matter to form alkaline condition, preferred described alkaline condition is for controlling pH 8～9.One of described alkaline matter is preferred following: sodium carbonate, salt of wormwood, sodium hydroxide, triethylamine, pyridine; More preferably alkaline matter is sodium carbonate, salt of wormwood or sodium hydroxide; Most preferably alkaline matter is sodium carbonate.Described alkaline matter can aqueous solution form add.
Step 2 of the present invention) in, the molar ratio of the chloro-2-butylene acid methyl esters of described 3-benzyloxy-4-and glycyl amide hydrochloride is 1:1～1.6; Be preferably 1:1～1.4.
Step 2 of the present invention) described ring-closure reaction can react between 20-200 ℃, and the reaction times is generally at 4～20 hours; Preferably ring-closure reaction temperature is 25-100 ℃, and the preferred reaction time is 8～15 hours; More preferably ring-closure reaction temperature is 50～70 ℃, and the reaction times is 13～15 hours.
Step 2 of the present invention) in, described separation and purification can adopt routine operation, for example: in gained reaction solution, add distilled water, stirring, suction filtration, obtain yellow thick crude product, this crude product obtains target product with recrystallization solvent recrystallization, and the target product purity obtaining is higher.Wherein said recrystallization solvent can be selected from the mixing of following one or both arbitrary proportions: ethanol, Virahol, water, toluene, methyl alcohol, acetone, sherwood oil, ethyl acetate or chloroform.
The concrete synthetic method of recommending described 2-(4-benzyloxy-2-oxo-2,5-pyrroline-1-yl)-ethanamide of the present invention is carried out in accordance with the following steps:
1) take the 4-chloro methyl acetoacetate shown in formula (1) as starting raw material, 4-chloro methyl acetoacetate and phenylcarbinol in non-protonic solvent under lewis acidic catalysis back flow reaction, gained reaction solution steams and desolventizes after completion of the reaction, obtain the chloro-2-butylene acid of the 3-benzyloxy-4-shown in formula (2) methyl esters, without the refining step 2 that is directly used in) reaction; It is one of following that described non-protonic solvent is selected from: hexanaphthene, benzene, toluene, dimethylbenzene; Described Lewis acid is tin tetrachloride; The molar ratio of described 4-chloro methyl acetoacetate and phenylcarbinol is 1:1～1.4; The described lewis acidic quality that adds is 1～5% of 4-chloro methyl acetoacetate quality;
2) the chloro-2-butylene acid methyl esters of the 3-benzyloxy-4-that is 1:1～1.4 by mol ratio and glycyl amide hydrochloride are dissolved in alcoholic solvent, and add alkaline matter regulation system pH 8～9, carry out ring-closure reaction in 50～70 ℃, react after 8～15 hours the add water stirring, suction filtration of gained reaction solution and obtain crude product, crude product obtains 2-(4-benzyloxy-2-oxo-2,5-pyrroline-1-yl)-ethanamide through recrystallization; Described alkaline matter is sodium carbonate, salt of wormwood or sodium hydroxide.
2-(4-benzyloxy-2-oxo-2 that the present invention is synthetic; 5-pyrroline-1-yl)-ethanamide can be used as the intermediate of synthesizing oxiracetam; can obtain oxiracetam by the protection of ordinary method debenzylation; for example reference literature Synthesis, 1985,76-77; Tetrahedron Lett.; the described method of 2005,46,7307-7309.
Compared with prior art, preparation method's of the present invention advantage is:
The synthesis step of oxiracetam intermediate 2-of the present invention (4-benzyloxy-2-oxo-2,5-pyrroline-1-yl)-ethanamide is short, easy and simple to handle, and raw material is cheap and easy to get, and product yield is high, quality good, and three waste discharge is few; And 2-(4-benzyloxy-2-oxo-2,5-pyrroline-1-yl)-ethanamide can obtain oxiracetam by simple debenzylation protection.Therefore, there is extraordinary prospects for commercial application with 2-(4-benzyloxy-2-oxo-2,5-pyrroline-1-yl)-ethanamide as the route of intermediate synthesizing oxiracetam.
(4) embodiment:
To the present invention be described in further detail with example below, certainly can not think that the present invention only limits to this example.
Synthesizing of embodiment 1 3-benzyloxy-4-chloro-2-butylene acid methyl esters.
Method 1: get tri-mouthfuls of round-bottomed flasks of dry 100mL, add 1.5g(0.01mol) the tosic acid acid of 4-chloro methyl acetoacetate, 1.08g (0.01mol) phenylcarbinol and 45mg, in this system, add 30mL hexanaphthene, magnetic agitation, oil bath heating, water trap refluxes, reaction 5h, be cooled to room temperature, decompression precipitation, obtains light yellow oily liquid, is the chloro-2-butylene acid of 3-benzyloxy-4-methyl esters, gas phase yield 15.20%, is directly used in the next step.
Method 2: get tri-mouthfuls of round-bottomed flasks of dry 100mL, add 1.5g(0.01mol) aluminum trichloride solution of 4-chloro methyl acetoacetate, 1.08g (0.01mol) phenylcarbinol and 5mL, in this system, add 30mL hexanaphthene, magnetic agitation, oil bath heating, water trap refluxes, reaction 5h, be cooled to room temperature, decompression precipitation, obtains light yellow oily liquid, is the chloro-2-butylene acid of 3-benzyloxy-4-methyl esters, gas phase yield 8.40%, is directly used in the next step.
Method 3: get tri-mouthfuls of round-bottomed flasks of dry 100mL, add 1.5g(0.01mol) tin tetrachloride of 4-chloro methyl acetoacetate, 1.08g (0.01mol) phenylcarbinol and 5mL, in this system, add 30mL hexanaphthene, magnetic agitation, oil bath heating, water trap refluxes, reaction 5h, be cooled to room temperature, decompression precipitation, obtains light yellow oily liquid, is the chloro-2-butylene acid of 3-benzyloxy-4-methyl esters, gas phase yield 56.38%, is directly used in the next step.
Method 4: get tri-mouthfuls of round-bottomed flasks of dry 100mL, add 1.5g(0.01mol) 4-chloro methyl acetoacetate, 1.08g (0.01mol) phenylcarbinol and 5mL1M HCl, in this system, add 30mL hexanaphthene, magnetic agitation, oil bath heating, water trap refluxes, reaction 5h, be cooled to room temperature, decompression precipitation, obtains light yellow oily liquid, is the chloro-2-butylene acid of 3-benzyloxy-4-methyl esters, gas phase yield 13.12%, is directly used in the next step.
Method 5: get tri-mouthfuls of round-bottomed flasks of dry 100mL, add 1.5g(0.01mol) tin tetrachloride of 4-chloro methyl acetoacetate, 1.08g (0.01mol) phenylcarbinol and 5mL, in this system, add 30mL toluene, magnetic agitation, oil bath heating, water trap refluxes, reaction 5h, be cooled to room temperature, decompression precipitation, obtains light yellow oily liquid, is the chloro-2-butylene acid of 3-benzyloxy-4-methyl esters, gas phase yield 68.92%, is directly used in the next step.
Synthesizing of embodiment 2 2-(4-benzyloxy-2-oxo-2,5-pyrroline-1-yl)-ethanamide 2.
The chloro-2-butylene acid of 3-benzyloxy-4-methyl esters, 1.12g (0.01mol) glycyl amide hydrochloride and 30mL methanol solvate that method 1. makes 2.40g (about 0.01mol) embodiment 1 are placed in 100mL there-necked flask, stir the lower 10mol/L of dropping sodium carbonate solution, the system pH of making remains between 8-9, after stirring 14h, the condition lower magnetic force that is 60 ℃ in temperature adds 15mL distilled water, stirring, suction filtration, obtain yellow thick crude product.Recrystallization solvent recrystallization several for this crude product, obtains yellow powdery solid, GC-MS:m/z=246[M]
+and only have a peak, productive rate is 70.26%.Fusing point: 247.2-248.6 ℃.
The chloro-2-butylene acid of 3-benzyloxy-4-methyl esters, 1.12g (0.01mol) glycyl amide hydrochloride and 30mL methanol solvate that method 2. makes 2.40g (about 0.01mol) embodiment 1 are placed in 100mL there-necked flask, stir the lower 10mol/L of dropping sodium hydroxide solution, the system pH of making remains between 8-9, after stirring 14h, the condition lower magnetic force that is 60 ℃ in temperature adds 15mL distilled water, stirring, suction filtration, obtain yellow thick crude product.Recrystallization solvent recrystallization several for this crude product, obtains yellow powdery solid, GC-MS:m/z=246[M]
+and only have a peak, productive rate is 67.52%.Fusing point: 246.5-248.0 ℃.
The chloro-2-butylene acid of 3-benzyloxy-4-methyl esters, 1.12g (0.01mol) glycyl amide hydrochloride and 30mL methanol solvate that method 3. makes 2.40g (about 0.01mol) embodiment 1 are placed in 100mL there-necked flask, stir the lower triethylamine solution that drips, the system pH of making remains between 8-9, after stirring 14h, the condition lower magnetic force that is 60 ℃ in temperature adds 15mL distilled water, stirring, suction filtration, obtain yellow thick crude product.Recrystallization solvent recrystallization several for this crude product, obtains yellow powdery solid, GC-MS:m/z=246[M]
+and only have a peak, productive rate is 56.78%.Fusing point: 246.4-247.5 ℃.
The chloro-2-butylene acid of 3-benzyloxy-4-methyl esters, 1.12g (0.01mol) glycyl amide hydrochloride and 30mL alcohol solvent that method 4. makes 2.40g (about 0.01mol) embodiment 1 are placed in 100mL there-necked flask, stir the lower 10mol/L of dropping sodium carbonate solution, the system pH of making remains between 8-9, after stirring 14h, the condition lower magnetic force that is 60 ℃ in temperature adds 15mL distilled water, stirring, suction filtration, obtain yellow thick crude product.Recrystallization solvent recrystallization several for this crude product, obtains yellow powdery solid, GC-MS:m/z=246[M]
+and only have a peak, productive rate is 75.52%.Fusing point: 246.8-247.9 ℃.
2-(4-benzyloxy-2-oxo-2,5-pyrroline-1-yl)-ethanamide 2 structural confirmations:
IR(KBr):3480,3968,1628,1600,1227cm
-1;
1H?NMR(CDCl
3，400MHz):1.56(s,2H,N-C
H 2-C-),3.23(s,2H,N-C
H 2-CO-),5.23(s,2H,PhC
H 2-O-),7.26(s,1H,=C
H-CO-),7.37(m,5H,Ar-
H);MS(70eV):m/z=246[M]
+.
Claims (8)
1. the synthetic method of a 2-(4-benzyloxy-2-oxo-2,5-pyrroline-1-yl)-ethanamide, comprises the steps:
1) take the 4-chloro methyl acetoacetate shown in formula (1) as starting raw material, 4-chloro methyl acetoacetate and phenylcarbinol in non-protonic solvent under lewis acidic catalysis back flow reaction, obtain the chloro-2-butylene of the 3-benzyloxy-4-shown in formula (2) acid methyl esters;
2) the chloro-2-butylene acid methyl esters of 3-benzyloxy-4-and glycyl amide hydrochloride carry out ring-closure reaction in polar solvent under alkaline condition, 20-200 ℃ temperature condition, fully after reaction, gained reaction solution obtains the 2-shown in target product formula (3) (4-benzyloxy-2-oxo-2,5-pyrroline-1-yl)-ethanamide through separation and purification;
2. 2-as claimed in claim 1 (4-benzyloxy-2-oxo-2,5-pyrroline-1-yl) synthetic method of-ethanamide, it is characterized in that: step 1) in, it is one of following that described non-protonic solvent is selected from: hexanaphthene, benzene,toluene,xylene, ether, dimethyl sulfoxide (DMSO), dimethyl formamide, acetone, acetonitrile.
3. 2-as claimed in claim 1 or 2 (4-benzyloxy-2-oxo-2,5-pyrroline-1-yl) synthetic method of-ethanamide, it is characterized in that: step 1) in, it is one of following that described Lewis acid is selected from: boron trifluoride, aluminum chloride, tin tetrachloride, iron(ic) chloride.
4. the synthetic method of 2-as claimed in claim 3 (4-benzyloxy-2-oxo-2,5-pyrroline-1-yl)-ethanamide, is characterized in that: step 1) in, described Lewis acid is tin tetrachloride.
5. the synthetic method of 2-as claimed in claim 1 (4-benzyloxy-2-oxo-2,5-pyrroline-1-yl)-ethanamide, is characterized in that: step 2) described polar solvent is alcoholic solvent.
6. (4-benzyloxy-2-oxo-2 of the 2-as described in claim 1 or 5,5-pyrroline-1-yl) synthetic method of-ethanamide, it is characterized in that: step 2) by adding alkaline matter to form pH at 8～9 alkaline condition, it is one of following that described alkaline matter is selected from: sodium carbonate, salt of wormwood, sodium hydroxide, triethylamine, pyridine.
7. the synthetic method of 2-as claimed in claim 1 (4-benzyloxy-2-oxo-2,5-pyrroline-1-yl)-ethanamide, is characterized in that: step 2) ring-closure reaction temperature is 25-100 ℃, the reaction times is 8～15 hours.
8. the synthetic method of 2-as claimed in claim 1 (4-benzyloxy-2-oxo-2,5-pyrroline-1-yl)-ethanamide, is characterized in that: described synthetic method is carried out in accordance with the following steps:
1) take the 4-chloro methyl acetoacetate shown in formula (1) as starting raw material, 4-chloro methyl acetoacetate and phenylcarbinol in non-protonic solvent under lewis acidic catalysis back flow reaction, gained reaction solution steams and desolventizes after completion of the reaction, obtain the chloro-2-butylene acid of the 3-benzyloxy-4-shown in formula (2) methyl esters, without the refining step 2 that is directly used in) reaction; It is one of following that described non-protonic solvent is selected from: hexanaphthene, benzene, toluene, dimethylbenzene; Described Lewis acid is tin tetrachloride; The molar ratio of described 4-chloro methyl acetoacetate and phenylcarbinol is 1:1～1.4; The described lewis acidic quality that adds is 1～5% of 4-chloro methyl acetoacetate quality;
2) the chloro-2-butylene acid methyl esters of the 3-benzyloxy-4-that is 1:1～1.4 by mol ratio and glycyl amide hydrochloride are dissolved in alcoholic solvent, and add alkaline matter regulation system pH 8～9, carry out ring-closure reaction in 50～70 ℃, react after 8～15 hours the add water stirring, suction filtration of gained reaction solution and obtain crude product, crude product obtains 2-(4-benzyloxy-2-oxo-2,5-pyrroline-1-yl)-ethanamide through recrystallization; Described alkaline matter is sodium carbonate, salt of wormwood or sodium hydroxide.
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