CN1015542B - Method of preparation of (r)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide - Google Patents
Method of preparation of (r)-alpha-ethyl-2-oxo-1-pyrrolidineacetamideInfo
- Publication number
- CN1015542B CN1015542B CN 85105307 CN85105307A CN1015542B CN 1015542 B CN1015542 B CN 1015542B CN 85105307 CN85105307 CN 85105307 CN 85105307 A CN85105307 A CN 85105307A CN 1015542 B CN1015542 B CN 1015542B
- Authority
- CN
- China
- Prior art keywords
- alpha
- ethyl
- formula
- oxo
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a method for preparing (R)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide X-CH2CH2-Y-NHCH(C2H5)CONH2(I) and a medical composition thereof. The compound can be prepared by that (R)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid reacts with halogenated alkyl formate, and then reacts with ammonia; or the compound can be prepared by cyclizing (R)-2-amino butyrylamide disclosed in the formula (I), wherein when X in the formula is ZOOC-, Y is-CH2-; when X is HalCH2-, Y is-CO-; Z is a C<1-4> alkyl group, and Hal is a halogen atom. Compared with a corresponding racemate, the dextro enantiomer has high memory effect and low toxicity.
Description
The invention relates to new compound-(R)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide and its preparation method.
English Patent No.1,309,692 have introduced compound alpha-ethyl-2-oxo-1-pyrrolidine acetamide (122 ℃ of fusing points), and point out that the type compound can be used for treatment, for example is used for treating movement disorders, hyperkinesis, hypertonia and epilepsy.
In addition, English Patent is also mentioned these compounds and can be applied to lethe under normal and the pathological situation.
Continue the research in this field, we prepare and have separated the dextrorotation enantiomorph of alpha-ethyl-2-oxo-1-pyrrolidine acetamide, and find that this dextrorotation enantiomorph is different from known racemic modification in the mode that does not reckon with fully.
(1) the memory efficiency ratio racemic modification of dextrorotation enantiomorph is high approximately 10 times,
(2) toxicity of dextrorotation enantiomorph is lower 3 times than racemic modification.
Because the dextrorotation enantiomorph has above-mentioned 2 unexpected characteristics, so alpha-ethyl-2-oxo-1-pyrrolidine acetamide dextrorotation enantiomorph is more suitable for being used for treating mental deficiency, lethe and study, the difficulty of studying and concentrating one's energy.
Therefore, the invention relates to the preparation absolute configuration is the method for dextrorotation enantiomorph of alpha-ethyl-2-oxo-1-pyrrolidine acetamide of R, and this compound does not contain the levo-enantiomer that absolute configuration is S in fact.
Can not be directly from racemic modification, obtain (R)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide of making according to the present invention by the method for separating two enantiomorphs.
According to the present invention, provide the method for (R)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide of preparation therapeutic activity.
First method comprises, make (R)-alpha-ethyl-2-oxo-the 1-pyrrolidine acetic acid has earlier the halo alkyl formate reaction of general expression HalCOOZ successively with (1), Hal represents halogen atom in the formula, and the Z representative has the alkyl of 1～4 carbon atom, again with (2) ammonia react.
Reaction is carried out in methylene dichloride in-10～-60 ℃ usually.
(R) that uses in reaction-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid can be taken racemic mixture apart by chemical process and make by original known method from racemic modification (±)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid.For example, (±)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid and optically active alkali reaction are formed salt, in appropriate solvent (as benzene), separate the salt that (R)-alpha-ethyl-2-oxo-the 1-pyrrolidine acetic acid is generated again with the continuous crystallisation method.
Can be used for taking apart racemic mixture, optically active alkali has alkaloids (as brucine, quinine, vauqueline, quinidine, cinchovatin) and amine (intending amine as Alpha-Methyl-benzylamine and dehydrogenation) (referring to SHWILEN etc., tetrahedron (Tetrahe-dron), 33, (1977), 2725～2736).Use Alpha-Methyl-benzylamine and dehydroabietylamine and can obtain satisfied especially result.
Racemic modification (±)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid as starting raw material can make by the corresponding alkyl esters of saponification, and it is synthetic at English Patent No.1, narration in 309,692.
Second method is included in inert solvent and alkaloid substance exists cyclisation down to have (R)-2-amino-butanamide of following formula
X-CH
2CH
2-Y-NHCH（C
2H
5）CONH
2（A）
In the formula, X represents ZOOC-or HalCH
2-Ji, Z are that alkyl, Hal with 1～4 carbon atom are halogen atom, Y representative-CH
2-or-the CO-base, when X represented the ZOOC-base, Y must be-CH
2-Ji is when X represents HalCH
2During-Ji, Y must be-the CO-base.
(R)-2-amino-butyramide (formula A) in inert solvent (as toluene or methylene dichloride), under the temperature of 0 ℃～solvent boiling point, carry out cyclisation.In the presence of alkaline matter, help carrying out cyclization as catalyzer.When formula A compound was ester (X=ZOOC-), catalyzer is 2 hydroxy pyrimidine preferably, (X=HalCH when formula A compound is halogen compound
2-), catalyzer is the bromination tetrabutylammonium preferably.
When X represents ZOOC-base and Y be-CH
2During-Ji, the compound of formula A is (R)-4-[(1-[aminocarboxyl) propyl group] amino] the butyric acid alkyl ester, general expression is ZOOCCH
2CH
2CH
2NHCH(C
2H
5) CONH
2, the definition of Z is the same in the formula.Make (R)-2-amino-butyramide and the condensation of 4-halo butyric acid alkyl ester, obtain (R)-4-[(1-(aminocarboxyl) propyl group] amino] the butyric acid alkyl ester, the general expression of 4-halo butyric acid alkyl ester is ZOOCCH
2CH
2CH
2Hal, in the formula definition of Z the same, Hal is a halogen atom.
When X represents HalCH
2-Ji, Y be-during the CO-base, formula A compound is (R)-N-[(1-aminocarboxyl) and propyl group]-4-halo butyramide, its general expression is HalCH
2CH
2CH
2CONHCH(C
2H
5) CONH
2The Hal definition is the same in the formula.By making (R)-2-amino-butyramide and the condensation of 4-halo butyryl halogen obtain (R)-N-[1-(aminocarboxyl) propyl group]-4-halo butyramide.The general expression of 4-halo butyryl halogen is HalCH
2CH
2CH
2COHal, Hal halogen atom in the formula.
(R)-reaction of the reaction of 2-amino-butyramide and 4-halo butyric acid alkyl ester or (R)-2-amino-butyramide and 4-halo butyric acid halogen generally all is in inert solvent (as benzene, toluene, methylene dichloride or acetone), in-5～+ 100 ℃, with at acid acceptor, as what carry out under organic tertiary base (as triethylamine) or mineral alkali (as salt of wormwood or potassium hydroxide, yellow soda ash or the sodium hydroxide) existence.
When X represents HalCH
2-Ji and Y be-during the CO-base, the formula A compound that obtains from above-mentioned raw material not necessarily will separate.In fact, the formula A compound that in reaction, obtains according to the present invention directly cyclisation be (R)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide
(the face example 4 as follows).
(R)-2-amino-butyramide as starting raw material can be separated the corresponding methyl esters of (R)-2-amino-butyric acid by ammonia and make according to KFOLKERS etc. in the described method of pharmaceutical chemistry magazine [(JMedchem) 14, (6), (1971), 484～87].
For the purpose of illustrating, provide following Example.
In the example, the optical purity of gained compound is measured special enthalpy and is proved (CFOUQUEY and JJACQUES, tetrahedron (Tetrahedroh), 23, (1967), 4009～19) by calorimeter below.
Example 1:
The preparation of (S)-Alpha-Methyl benzylamine salt of (a), (R)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid.
In 4 liters of flasks, 513 gram (3 moles) racemic modification (±)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acids are suspended in 1.26 liters of dry-out benzene.In addition with 181.5 grams (1.5 moles) (S)-(-)-Alpha-Methyl benzylamine and 151.8 gram (1.5 moles) triethylamines are dissolved in 2 liters of dry-out benzene, and this solution are added above-mentioned suspension.The mixed solution reflux is up to dissolving fully then.Cooling also makes crystallization a few hours.Leach crystallization, and with 400 milliliters of benzene washed twice, (S)-Alpha-Methyl benzylamine salt of 337 gram (R)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acids.
Fusing point: 145～149 ℃.Productive rate: 76.9%.
This salt can reflux carry out purifying in 4 hours in 3 liters of benzene liquid.Cooled and filtered gets the needed salt of 297.7 grams.
Fusing point: 149～152 ℃.Productive rate: 68%.
(b), the preparation of (R)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid, the salt of 297.7 grams by (a) preparation are dissolved in 0.6 premium on currency, add 147.3 grams, 30% sodium hydroxide solution lentamente, make the pH of solution reach 12.6, temperature is no more than 25 ℃.Then with solution restir 20 minutes, the Alpha-Methyl-benzylamine of separating out is with 150 milliliters of benzene extraction seven times.
Water is with 188 milliliters of 6N hcl acidifyings, and making pH is 1.1.
Mixture was stirred 45 minutes, and the acid of separating out is with 200 milliliters of dichloromethane extraction five times. the merging organic phase, and use dried over mgso.Boil off behind the solvent 170.5 grams (R) ,-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid.
Fusing point: 126 ℃ (α)
20 D:+27.3 ° (C=1, acetone).Productive rate: 98%.
The preparation of (c), (R)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide.With 17.1 grams (0.1 mole) (R)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid is suspended in 100 milliliters and is cooled in-13 ℃ the methylene dichloride, is added dropwise to 13.9 milliliters of triethylamines again.9.56 milliliters of chloro ethyl formates are added in the above-mentioned solution that makes, and the speed of dropping should make temperature of reaction be no more than-13 ℃.Reaction mixture stirs half an hour, feeds ammonia then about 2.5 hours.
Make the temperature of reaction mixture get back to room temperature, leach the ammonium salt of generation, use washed with dichloromethane.Boil off solvent, residue is used re-crystallizing in ethyl acetate in the presence of the 10 Powdered molecular sieves of gram (0.3～0.4 millimicron).
Obtain 11.2 gram (R)-alpha-ethyl-2-oxo-1-pyrrolidine acetamides.Fusing point: 115～117 ℃.(α)
25 D:+90.7(C=1, acetone).Productive rate: 66%.Analyze: C
8H
14N
2O
2
Calculated value (%): C56.45 H8.29 N16.46
Analytical value (%): 56.38 8.36 16.43
Being used for (a) synthetic racemic modification (±)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid prepares with following method.
788 gram (19.7 moles) sodium hydroxide are dissolved in 4.35 premium on currency, then this sodium hydroxide solution is added in 20 liters of flasks that 3.65 kilograms of (18.34 moles) (±)-alpha-ethyl-2-oxos-1-pyrrolidine acetic acid ethyl ester is housed, added with interior at 2 hours, and make temperature be no more than 60 ℃.After sodium hydroxide solution adds, make the temperature of mixture rise to 80 ℃, steam the ethanol of generation, reach 100 ℃ up to the temperature of reaction mixture.
Reaction mixture is cooled to 0 ℃, in 2.5 hours, adds 1.66 liters of (19.80 moles) 12N hydrochloric acid.The sedimentation and filtration that generates is collected, and with 2 liters of toluene wash, and uses the Virahol recrystallization.Get 2.447 kilograms of racemic modifications (±)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid, 155～156 ℃ of fusing points.
Productive rate: 78%.
Analyze: C
8H
13NO
3
Calculated value (%): C56.12 H7.65 N8.18
Analytical value (%): 55.82 8.10 7.97
Example 2:
(a), propyl group (R)-4-[(1-(aminocarboxyl)] amino] preparation of ethyl butyrate
With 47.75 the gram (0.345 mole) (R)-2-amino-butanamide hydrochloride ((α)
25 D;-26.1 °; C=1, methyl alcohol) be suspended in 400 milliliters of toluene, add 143.6 milliliters of (1.035 moles) triethylamines then,, and drip 67.2 gram (0.345 mole) 4-bromo ethyl butyrates mixture heating up to 80 ℃.
Reaction mixture kept 10 hours at 80 ℃, and filtered while hot is to remove triethylamine salt.After the filtrate evaporated under reduced pressure, obtain 59 grams and mainly form, but also contain the oily residue of a small amount of dialkyl group derivative by monoalkylated product.
The thick product that obtains can be used for by cyclisation preparation (R)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide without being further purified.
The preparation of (b), (R)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide
The thick product that 54 grams are obtained by above-mentioned (a) in the presence of 2 gram 2 hydroxy pyrimidines, is dissolved in 125 milliliters of toluene.This mixture kept 12 hours at 110 ℃.
A small amount of insolubles filtered while hot is removed, and filtrate decompression concentrates.
Make residue by the chromatography column that 1.1 kilograms of silica gel are housed purifying (column diameter: 5 centimetres; Elutriant; The mixture of ethyl acetate, methyl alcohol and strong aqua, volume ratio are 85: 12: 3).
The product that separation obtains gets 17.5 gram (R)-alpha-ethyl-2-oxo-1-pyrrolidine acetamides with 50 milliliters of re-crystallizing in ethyl acetate.
Fusing point: 117 ℃, (α)
25 D:+90.0 ° (C=1, acetone).
Productive rate: 41.2%.
Example 3:
(a), propyl group (R)-N-(1-(aminocarboxyl))-preparation of 4-neoprene acid amides
In 160 milliliters of acetone, with the salt of wormwood of 31.1 gram (0.225 mole) porphyrizes and 12.47 grams (0.09 mole) (R)-the 2-amino-butanamide hydrochloride mixes.Reaction mixture is cooled to 0 ℃, and splashes into 15.23 gram (0.108 mole) 4-chlorobutanoylchlorides and 25 milliliters of solution that acetone is formed, and finishes, and allows the temperature of reaction mixture get back to room temperature.Insolubles removes by filter, and filtrate decompression concentrates.The thick residue that obtains stirred 15 minutes in 5～10 ℃ in 100 milliliters of anhydrous diethyl ethers.Leach precipitation,, get 16 gram (R)-N-(1-(aminocarboxyls with 30 milliliters of ether washing secondaries, vacuum-drying) propyl group)-4-neoprene acid amides.
Fusing point: 127～129 ℃.(α)
25 D:+22.2 ° (C=1, methyl alcohol).
Productive rate: 86%.
The preparation of (b), (R)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide
6.2 the gram (0.03 mole) (R)-the N-[1-(aminocarboxyl) propyl group]-4-neoprene acid amides and 0.484 the gram (0.0015 mole) bromination tetrabutylammonium in 42 milliliters of methylene dichloride, under nitrogen, mixes in 0 ℃.Add 2.02 gram (0.036 mole) potassium hydroxide powder, in 30 minutes, add, the speed of adding should make the temperature of reaction mixture be no more than+2 ℃.Mixture was stirred 15 minutes, make temperature get back to room temperature then.Insoluble material removes by filter, and filtrate decompression concentrates.The residue that obtains stirred 30 minutes in 25 milliliters of tetracol phenixin, leached then and drying.Product is in the presence of the molecular sieve of 0.4 millimicron of 1.7 gram, and with 45 milliliters of re-crystallizing in ethyl acetate, filtered while hot is removed molecular sieve, gets 3.85 gram (R)-alpha-ethyl-2-oxo-1-pyrrolidine acetamides.
Fusing point: 116～118 ℃.(α)
25 D:+89.8 ° (C=1, acetone).
Productive rate: 75.4%.
Example 4:
(R)-preparation of alpha-ethyl-2-oxo-1-pyrrolidine acetamide
The other method of this example narration preparation example 3 products, resulting in this example intermediate 4-neoprene acid amides is without separation.
The logical nitrogen under room temperature with 23 gram powder potassium hydroxide and 9 gram Hyflo-Cel, and vigorous stirring, be incorporated in 13.86 grams (0.1 mole) (R)-suspension that 2-amino-butanamide hydrochloride and 60 milliliters of methylene dichloride are formed in.
Reaction mixture stirred 1 hour, and temperature drops to about 5 ℃ then, added 6.52 gram (0.02 mole) bromination tetrabutylammoniums then, then 3 hours with interior adding by 12.46 milliliters of 4-chlorobutanoylchlorides and 25 milliliters of solution that methylene dichloride is formed.Reaction mixture makes temperature get back to room temperature 5 ℃ of restir 1 hour then, continues to stir 23 hours.
Reaction mixture filters, the organic phase concentrating under reduced pressure.
Residue is dissolved in the toluene (400% volume/weight) of heat, and mixture filters.The solid thermal that obtains is dissolved in the ethyl acetate (400% volume/weight), adds 0.4 millimicron of Powdered molecular sieve (32% w/w) in above-mentioned solution.Mixture heating up is to reflux temperature, and filtered while hot.After the filtrate cooling, desired product crystallizes out, and gets 9.18 gram (R)-alpha-ethyl-2-oxo-1-pyrrolidine acetamides.
Fusing point: 117 ℃.(α)
25 D:+89.7 ℃ (C=1, acetone).
Productive rate: 54%.
Pharmacological testing
Racemic alpha-ethyl-2-oxo-1-pyrrolidine acetamide (compd A) and (R) of the present invention-alpha-ethyl-2-oxo-1-pyrrolidine acetamide (compd B) has all passed through pharmacological testing.
The usefulness of I, memory
Memory usefulness is [SJSARA and MDAVID, psychopharmacology (Psychopharmacologia), 36, (1974), 59～66] that illustrate with the test short of money to the effect of electroshock inductive lethe.
Test principle is as follows:
When the big white mouse claw stands pressure mark in advance, that increase gradually, can observe the contractile response of big white mouse claw.Make the pressure that contractile response takes place be called " threshold of reaction " (reaction thershold).This threshold value can be directly scale from used instrument (the UGO BASILE Milan analgesia meter) scale card show, this threshold value is equivalent to the minimum pressure values [learning period (Learning Session)] that is used for the animal claw and causes contraction.Measure each 30 minutes at interval three times.
Learning period finishes 24 hours afterwards, tests, and control animals reveals inherent memory to above-mentioned test card, and its threshold value is equivalent to scale 8～10.
After the learning period finishes to 15 minutes of short duration maximal electroshocks of big white mouse (100 milliliters, 120 volts, 0.2 second), to induce the lethe effect.When measuring memory later on when 24 hours, because electroshock inductive disappearance effect, cause avoiding the increase of threshold value (avoidance threshold), this avoidance threshold value is equivalent to be used for first the threshold value of the animal (not passing through the animal of learning period) of doing experiment, that is to say that threshold value is on the scale between 14～19.
Not back 24 hours of learning period, in standing the animal of electroshock, measure each test-compound, rebuild the minimum effective dose (with milligram/kilogram calculate) of scale in 8～10 normality threshold.
After the learning period finishes 5 minutes, give the solution or the suspension of the subcutaneous injection test-compound 10% of test big white mouse, every group of big white mouse is 10 (weighing the 150 female Wistar big white mouse that restrain).10 big white mouse control groups are only given 0.9% sodium chloride aqueous solution simultaneously.
Evidence, dextrorotation enantiomorph of the present invention (compd B) prevent that animal electricity shock inductive lethe efficiency ratio racemic modification (compd A) is strong 10 times.
The effective agent energy of test-compound (milligram/kilogram)
A 1.70
B 0.17
II, toxicity
At male white mouse and male white rat upper vein injection compd A and B, the LD that records
50Value (with milligram/kilogram expression) sees the following form:
Test-compound LD
50(milligram/kilogram)
The small white mouse big white mouse
A 1790 1500
B 5603 5000
From this table as seen, the toxicity of dextrorotation enantiomorph of the present invention (compd B) is littler three times than racemic modification (compd A).
The compound of being invented can solid for mulation or taken with forms of liquid compositions, and is for example oral with tablet, pill, coated tablet, capsule, solution or syrup form, perhaps with solution or suspensoid form drug administration by injection.
Preparation such as solution or tablet, available ordinary preparation method makes.Compound of the present invention can mix with acceptable solid on nontoxic, the preparation or liquid vehicle, and can at random mix with dispersion agent, stablizer.Can add pigment, sweeting agent etc. when needing.
Equally, solid or the liquid medicine carrier that is applied in these compositions all is known.The solid pharmaceutical vehicle that for example prepares tablet or capsule has starch, talcum powder, lime carbonate, lactose, sucrose, Magnesium Stearate etc.According to the mode and the patient of drug administration, the percentage composition of effective constituent can change within a large range in pharmaceutical composition.
Every day human dosage can 250 milligrams and 4 the gram between.The prescription that contains the example-oral drink soln of the composition of The compounds of this invention and zero capsule agent is as follows,
The ampoule drink soln
Compd B 2.5 grams
Sorbyl alcohol (70% aqueous solution) 3.0 grams
Glycerine 2.5 grams
Glgcamil 0.025 gram
Para methyl paraben 0.0135 gram
Propylparaben 0.0015 gram
Sodium saccharinate 0.06 gram
Liquorice essence 0.05 gram
Purify waste water and be added to 10 milliliters
Weigh 500 milligrams zero capsule
500 milligrams of compd Bs
Avicel(X) 50 milligrams
5 milligrams of magnesium stearates
(X) be Microcrystalline Cellulose
To recall disappearance in order treating with the aging relevant mankind, to propose to use composite treatment recently, this method comprises taking and can strengthen the metabolic medicine of brain, as nootropyl (2-OXo-1-pyrrolidine ethanamide) and choline precursor, as lecithin or choline salt.
US Patent specification № 4,385, and 053 introduces, and nootropyl and choline precursor have synergy, can obviously improve the elderly's lethe, especially to improving the alzheimer's (lethe of senile dementia of Alzh-oimer ' s).
We find now, have similar synergy between dextrorotation enantiomorph of the present invention and the choline precursor.Therefore, the dextrorotation enantiomorph and the central nervous system cholinergic precursor that make by the present invention are used in combination, can be effectively used to treat the illnesss such as lethe of aging, alzheimer's senile dementia equally, so that make learning and memory ability and general thinking ability obtain useful clinical effectiveness.
About cholinergic precursor, not only be interpreted as choline or its salt, and comprise any material that in organism, can discharge choline, for example Yelkin TTS (Lecithin) or phosphatidylcholine (Phos Ptiatidgl Choline).In order to obtain desirable usefulness, this precursor must improve choline level in the blood, and can improve the availability of choline synthesis of acetyl choline in brain simultaneously.
When dextrorotation enantiomorph of the present invention and cholinergic precursor share, the dextrorotation enantiomorph can be taken before or after this precursor is taken.Therefore, dextrorotation enantiomorph and precursor can be taken simultaneously, or take respectively, or take in for some time.Preferably take simultaneously.
And the route of administration of dextrorotation enantiomorph of the present invention can be identical or different with the route of administration of cholinergic precursor.Evidence is effective especially with oral these two compounds of common dosage form (tablet, capsule, solution).Dextrorotation enantiomorph of the present invention and cholinergic precursor can also be taken with single dosage unit form simultaneously.
Show that in the detailed application form of the present invention the dextrorotation enantiomorph is preferably oral, the dosage that restrain every day 100 milligrams～4, and cholinergic precursor is also preferably oral, can supply with the dosage of patient's 1～10 gram choline every day.For example take 2～25 gram phosphatidylcholines or 1～30 gram choline salt every day.In the healthy volunteer, simultaneously once oral 1.5 gram dextrorotation enantiomorphs of the present invention and 25 gram Yelkin TTS (18 gram phosphatidylcholine) afterwards, find that by the quantitative analysis electroencephalogram dextrorotation enantiomorph of the present invention and Yelkin TTS have synergy.
Claims (4)
1, the method for a kind of preparation (R)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide, this method is included in the methylene dichloride and reaches-10 ℃～-60 ℃, make (R)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid and (1) has the halo alkyl formate reaction of formula Halcooz (Hal represents halogen atom in the formula, z represents the alkyl of 1-4 carbon atom), again with (2) ammonia react.
2, the method for a kind of preparation (R)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide, this method are included in and reach in the inert solvent having in the presence of the alkaline matter, under the boiling point of 0 ℃～solvent, and cyclisation following formula (R)-2-amino-butanamide,
X-CH
2CH
2-Y-NHCH（C
2H
5）CONH
2（A）
X represents ZOOC-or HaICH in the formula
2-Ji, Z are that alkyl and HaI with 1-4 carbon atom are halogen atom, Y representative-CH
2-or the CO-base, condition is that Y is-CH when X represents the ZOOC-base
2-Ji; When X represents HaICH
aDuring-Ji, Y is-the CO-base.
3, according to the described method of claim 2, its Chinese style A compound is formula ZOOCCH
2CH
2CH
2NHCH(C
2H
5) CONH
2(R)-4-((1-(aminocarboxyl) propyl group) amino)-the butyric acid alkyl ester, and get by (R)-2-amino-butanamide and 4-halo butyric acid alkyl ester condensation with following formula,
ZOOCCH
2CH
2CH
2Hal，
The definition of Z is with claim 2, and HaL is a halogen atom, and alkaline matter is 2 hydroxy pyrimidine, and inert solvent is a toluene.
4, according to the described method of claim 2, its Chinese style A compound is formula HAlCH
2CH
2CH
2CONHCH(C
2H
3) CONH
2(R)-N-(1-(aminocarboxyl) propyl group)-4-halo butyramide, and by (R)-2-amino-butanamide and formula HalCH
2CH
2CH
2The 4-halo butyryl halogenide condensation of COHal and getting, Hal is a halogen atom in the formula, and alkaline matter is the mixture of Tetrabutyl amonium bromide and potassium hydroxide, and inert solvent is a methylene dichloride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 85105307 CN1015542B (en) | 1984-05-15 | 1985-07-10 | Method of preparation of (r)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB848412358A GB8412358D0 (en) | 1984-05-15 | 1984-05-15 | Pharmaceutical composition |
| CN 85105307 CN1015542B (en) | 1984-05-15 | 1985-07-10 | Method of preparation of (r)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN85105307A CN85105307A (en) | 1987-01-14 |
| CN1015542B true CN1015542B (en) | 1992-02-19 |
Family
ID=25741860
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 85105307 Expired CN1015542B (en) | 1984-05-15 | 1985-07-10 | Method of preparation of (r)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1015542B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1303066C (en) * | 2000-02-23 | 2007-03-07 | Ucb公司 | 2-oxo-1-pyrrolidine derivatives, process for preparing them and their uses |
-
1985
- 1985-07-10 CN CN 85105307 patent/CN1015542B/en not_active Expired
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1303066C (en) * | 2000-02-23 | 2007-03-07 | Ucb公司 | 2-oxo-1-pyrrolidine derivatives, process for preparing them and their uses |
Also Published As
| Publication number | Publication date |
|---|---|
| CN85105307A (en) | 1987-01-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100369894C (en) | Nitric oxide synthase inhibitor phosphate salt | |
| CN1149190C (en) | Nitric oxide synthase inhibitors | |
| CN85105301A (en) | (S)-preparation method of alpha-ethyl-2-oxo-1-pyrrolidine acetamide | |
| CN1014516B (en) | Phenyl ethers | |
| CN1042331C (en) | Indole derivatives | |
| US5420155A (en) | Tetramic acid derivatives | |
| CN1272319C (en) | Process for making amlodipine maleate | |
| WO2017066705A1 (en) | Compounds, compositions and methods of use against stress granules | |
| CN1089838A (en) | The syndromic pharmaceutical composition of a kind of control motion sickness | |
| CN1360591A (en) | 3 alpha-hydroxy-3 beta-methoxymethyl-21-heterocycle substd. steroids with anesthetic activity | |
| DE69811360T2 (en) | DIAZEPINOINDOLONE AS A PHOPHODIESTERASE 4 INHIBITORS | |
| CN1067884A (en) | Pyrimidine-4-carboxamides derivatives and method for making and medical applications | |
| ES2368786T3 (en) | CRYSTAL BASE OF TRANS-1 - ((1R, 3S) -6-CHLORO-3-FENILINDAN-1-IL) -3,3-DIMETHYLIPIPERAZINE. | |
| TWI822457B (en) | DP antagonist | |
| CA2861891C (en) | Crystal form of (6s)-5-methyltetrahydrofolate salt and method for preparing same | |
| CN87106996A (en) | Quinoline compound, their preparation method and with its carcinostatic agent as the active drug component | |
| CN1227538A (en) | Pharmaceutical composition containing 4-oxo-butynic acid | |
| CN1114592C (en) | Crystalline forms of osanetant | |
| CN1015542B (en) | Method of preparation of (r)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide | |
| JPH0368574A (en) | Pharmaceutically active aminoimidazopyridine | |
| CN1720248A (en) | Crystalline fumarate salts of 1-azabicyclo[2.2.2]oct substituted furo[2,3-c]pyridinyl carboxamide and compositions and preparations thereof | |
| CN109999033B (en) | Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and uses thereof | |
| CN1375494A (en) | Iso-indolo-indolone compound, their preparation methods and drug compositions comprising the same | |
| JPH01151592A (en) | Novel phosphinic acid derivative and ameliorating agent of cerebral circulation metabolism containing said derivative as active ingredient | |
| CN1120036A (en) | N-substituting group-4-substituted benzyl-5-alkyl-5-substituted benzyl-pyrrolidone-2, and its intermediate, its synthetic method and its appliance |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C13 | Decision | ||
| GR02 | Examined patent application | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |