CN106478482A - A kind of synthetic method of Oxiracetam - Google Patents
A kind of synthetic method of Oxiracetam Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
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Abstract
A kind of synthetic method of (S) Oxiracetam, comprises the steps：(1) with 4 amino of S, 3 hydroxybutyric acid as initiation material, esterification is carried out with alcohol, obtain intermediate compound I；(2) intermediate compound I and halogenated acetic acids ester are carried out condensation reaction, obtains intermediate II；(3) intermediate II is carried out ring closure reaction and obtains intermediate III；(4) intermediate III is carried out ammonolysis reaction, obtains target product (S) Oxiracetam.Oxiracetam synthetic route of the present invention can at least obtain (S) Oxiracetam product of more than 20% more satisfactory yield, open a new Oxiracetam synthetic route.
Description
The application is Application No. " 201310243165.7 ", entitled " a kind of synthetic method of Oxiracetam "
The divisional application of application for a patent for invention.
Technical field
The present invention relates to a kind of synthetic method of Oxiracetam, more particularly to a kind of synthetic method of (S)-Oxiracetam.
Background technology
Oxiracetam be by Italian SmithKline than the cereboactive drug that Qie Mu company synthesized first in 1974, be by two kinds of isomeries
The raceme that body (S)-Oxiracetam ((S)-oxiracetam) and (R)-Oxiracetam ((R)-oxiracetam) constitute.(S)-
Oxiracetam is a single enantiomer of Oxiracetam, and chemistry is entitled：(S) -2 oxo-1-pyrrolidine ethanamide of -4- hydroxyl.
Nootropic Oxiracetam is a kind of the hydroxy-amino-butyric acid of synthesis (GABOB) derivative, and it is that one kind can promote study, strengthens note
Recall power, protect the medicine for central nervous system of damaged nerve cell.
At present, the method for synthesis (the S)-Oxiracetam of document report has four kinds：
United States Patent (USP) US4173569 has addressed a kind of synthetic method of (S)-Oxiracetam：(S) -4- amino -3- hydroxyl fourth
Acid is initiation material, protects hydroxyl through sillylation reagent, and the product after cyclization is reacted with halogenated acetic acids ethyl ester, product
Through Deprotection, ammonolysis, target compound is finally obtained.This kind of preparation method is not suitable for industrial-scale production, because it
Have disadvantages that, such as carrying out protection using protection group to hydroxyl can increase reactions steps, waste raw material, time-consuming longer, increase into
This, reduces total recovery.In addition, in this course of reaction, needing column chromatography purifying to be carried out to intermediate, can just carry out next step
Reaction.These shortcomings are all very unfavorable for industrial-scale production.
Document：Tetrahedron:Asymmetry 1992,3 (11) reports a kind of method for synthesizing the compound；With
Malic acid and glycine methyl ester are initiation material, and chloroacetic chloride protects hydroxyl, and chosen property is reduced, and removes hydroxyl, Deprotection, ammonia
Solution, obtains target compound.In this approach, need to carry out a selective reduction and the multiple accessory substances of generation are caused, and
Each intermediate is required for column chromatography to purify, and can just carry out next step reaction.Such technique can not equally meet industrialization
The requirement of scale.
Technology disclosed in patent W02005/115978, wherein (S) -4- chloro-3-hydroxyl ethyl butyrate are reacted with glycine amide
Target compound is obtained, or is reacted with glycine ethyl ester, then target compound is obtained through ammonolysis.The wherein chloro- 3- hydroxyl of (S) -4-
Base butyrate reacted with sweet amine amide in the basic conditions obtain final products Oxiracetam be by disposably plus alkali is controlling
The alkalescence of reactant liquor, but as Oxiracetam is more easily damaged in strong base solution, so directly affects the pure of Oxiracetam
Degree and yield；In addition silica gel column chromatography method is adopted in purifying final products Oxiracetam, the eluent for using is organic mixed
Bonding solvent, quantity of solvent are big, be not easily recycled, high cost, and silica gel column chromatography method is also not suitable for industrial amplification production.
Chinese patent CN10575309A is reported one kind and is carried out as raw material with glycine and S-4- halogen -3-hydroxybutyrate ester
Condensation, then carry out being esterified the synthetic route of ammonolysis, but the method is carried out by the way of equally dripping highly basic under hot conditions
Condensation, can cause condensation yield relatively low with multiple side reactions such as S-4- halogen -3-hydroxybutyrate ester hydrolysis while condensation,
Accessory substance is more, obtain end-product S-oxiracetam under the purity cannot direct crystallization separate out, need ion exchange resin
Chromatography removal of impurities, high cost, purity are low, it is difficult to industrialize.
Content of the invention
It is an object of the invention to provide a kind of synthetic method of Oxiracetam, the inventive method is simple to operate, purity is high,
High income.
The object of the invention is achieved through the following technical solutions：
A kind of synthetic method of (S)-Oxiracetam, comprises the steps：
(1) with S-4- amino -3-hydroxybutyrate as initiation material, esterification is carried out with alcohol, obtain intermediate compound I；
(2) intermediate compound I and halogenated acetic acids ester are carried out condensation reaction, obtains intermediate II；
(3) intermediate II is carried out ring closure reaction and obtains intermediate III；
(4) intermediate III is carried out ammonolysis reaction, obtains target product (S)-Oxiracetam.
Reaction expression is as follows：
Inventor is studied through long-term experiment, has been attempted a lot of new synthesis routes and has all been difficult to obtain (S)-Oxiracetam, most
Above synthetic route is pressed eventually, by the cooperation of each reaction type and sequencing above so as to obtain more than 20% more satisfactory yield
(S)-Oxiracetam product, open a new Oxiracetam synthetic route.
In order that impurity is more easily separated, operating procedure simple, so as to obtaining high-purity product, promoting the work of pharmaceutical production
Industry, while also ensureing reaction yield, the halogenated acetic acids ester in above-mentioned steps (2) preferably adopts bromoacetate, monoxone second
Ester, bromoacetic acid N-butyl, bromide isobutyl acetate, bromo-acetic acid tert-butyl or benzyl acetate bromide.
In order to improve reactivity further, so as to improve reaction yield further, above-mentioned (1) is preferably a step：
S-4- amino -3-hydroxybutyrate is added in alcohol, also under conditions of acylating agent or catalyst is instilled, is esterified
Reaction obtains intermediate compound I；The optional methyl alcohol of the alcohol, ethanol, normal propyl alcohol, isopropanol, n-butanol, the tert-butyl alcohol, cyclohexanol or ring penta
Alcohol, it is preferred to use methyl alcohol, ethanol, normal propyl alcohol or cyclopentanol；The acylating agent is concentrated hydrochloric acid, the concentrated sulfuric acid, thionyl chloride, trichlorine oxygen
Phosphorus, phosphorus pentachloride or oxalyl chloride；The catalyst is the concentrated sulfuric acid, Loprazolam, p-methyl benzenesulfonic acid or trifluoroacetic acid.
Intermediate compound I formula is as follows：
R1 is methyl, ethyl, n-propyl, isopropyl, normal-butyl, the tert-butyl group, isobutyl group, cyclopenta or cyclohexyl etc..
In order to further improve reactivity, raising reaction yield, above-mentioned acylating agent or catalyst and S-4- amino -3-
The mol ratio of hydroxybutyric acid is：S-4- amino -3-hydroxybutyrate：Acylating agent or catalyst=1：1～2.5.
More specifically, above-mentioned (1) step is：
First S-4- amino -3-hydroxybutyrate is mixed with the above-mentioned alcohol of 5～20 times of weight, be subsequently adding above-mentioned acylating agent or
Catalyst is reacted 1～5 hour at 0～60 DEG C, and S-4- amino -3-hydroxybutyrate is 1 with acylating agent or catalyst molar ratio：
1.5～1.65；The alcoholic solution containing intermediate compound I is obtained, from the alcoholic solution containing intermediate compound I, then collects intermediate compound I.
Above-mentioned S-4- amino -3-hydroxybutyrate, alcohol and acylating reagent is commercially available prod.
Above-mentioned (2) step, specifically, is the intermediate compound I that will be obtained from step (1), in a solvent with halogenated acetic acids ester
React 5～10 hours in the presence of base catalyst, reaction temperature is 0～60 DEG C, then collect and obtain intermediate II；The solvent
Nothing particular/special requirement, prioritizing selection methyl alcohol, ethanol, isopropanol, tetrahydrofuran, one or more combination in DMF, DMSO；Described
Base catalyst be preferably pyridine, triethylamine, lutidines, potassium carbonate or sodium acid carbonate.
In order to further improve reaction purity and yield, intermediate compound I with the mol ratio of halogenated acetic acids ester is：1:1～3,
Intermediate compound I with the mol ratio of the base catalyst is：1:2～3.
Most specifically say that above-mentioned (2) step is the intermediate compound I that will be obtained from step (1), in S-4- amino -3- hydroxyl fourth
React 5～10 hours in the presence of base catalyst with halogenated acetic acids ester in the solvent of the 10-15 times of weight of acid, reaction temperature is 0
～60 DEG C, then collect and obtain intermediate II；The solvent is nothing particular/special requirement, prioritizing selection methyl alcohol, ethanol, isopropanol, tetrahydrochysene
One or more combination in furans, DMF, DMSO；Described base catalyst is preferably pyridine, triethylamine, lutidines, carbon
Sour potassium or sodium acid carbonate；Intermediate compound I with the mol ratio of halogenated acetic acids ester is：1:1～3, intermediate compound I is rubbed with the base catalyst
You are at ratio：1:2～3.
Intermediate II formula is as follows：
R1 is methyl, ethyl, n-propyl, isopropyl, normal-butyl, the tert-butyl group, isobutyl group, cyclopenta or cyclohexyl etc.；
R2 is ethyl, n-propyl, isopropyl, normal-butyl, the tert-butyl group, isobutyl group, benzyl or cyclopenta etc..
Above-mentioned steps (3), specifically, intermediate II that step (2) is obtained, in a solvent under the conditions of 50～130 DEG C
Ring closure reaction is carried out, the time is 3～8 hours, the solution containing intermediate III is obtained, then from the solution containing intermediate III
Collection obtains intermediate III；Described solvent may be selected：Ethanol, the tert-butyl alcohol, toluene, dimethylbenzene, water, ethyl acetate, acetic acid fourth
Ester or ethyl butyrate, it is preferred to use ethanol, toluene or dimethylbenzene.
III formula of intermediate is as follows：
R2 is ethyl, n-propyl, isopropyl, normal-butyl, the tert-butyl group, isobutyl group, benzyl or methoxybenzyl etc..
In order to further improve reaction purity and yield, intermediate II is 1 with the mol ratio of solvent：10～30.
Above-mentioned steps (4), specifically, intermediate III that step (3) is obtained, is reacted with concentrated ammonia liquor at 20～30 DEG C
4～16 hours, from product, then collect target product (S)-Oxiracetam.
In order to improve reactivity further so as to improve overall yield of reaction, above-mentioned intermediate III：During the mol ratio of ammonia is
Mesosome III：Ammonia=1：12～15, in terms of the ammonia in ammonia methanol solution；Described concentrated ammonia liquor is known in the art, its solution
Concentrations by weight be 25～28% or so.
The method for collecting target product (S)-Oxiracetam from the product of above-mentioned steps (4), is preferably walked as following
Suddenly：Product is dissolved in the water, heating for dissolving, activated carbon decolorizing, activated carbon is filtered to remove, reduced pressure concentration eliminating water, when surplus
Stop concentrating when remaining water is for adding 2～3 times of products weight, 0～5 DEG C of sub-cooled crystallization, obtain to obtain product (S)-Aura west
Smooth.
A kind of synthetic method of DL body Oxiracetam, it is characterised in that comprise the steps：
(1) with 4- amino -3-hydroxybutyrate as initiation material, esterification is carried out with alcohol, obtain intermediate compound I；
(2) intermediate compound I and halogenated acetic acids ester are carried out condensation reaction, obtains intermediate II；
(3) intermediate II is carried out ring closure reaction and obtains intermediate III；
(4) intermediate III is carried out ammonolysis reaction, obtains target product Oxiracetam.
Inventor has attempted a lot of new synthesis routes and has all been difficult to obtain Oxiracetam, finally presses above synthetic route, passes through
The cooperation of each reaction type and sequencing is opened so as to obtain the Oxiracetam product of more than 20% more satisfactory yield above
One new Oxiracetam synthetic route.
Preferably, the halogenated acetic acids ester in above-mentioned steps (2) preferably adopts bromoacetate, ethyl chloroacetate, bromoacetic acid
N-butyl, bromide isobutyl acetate, bromo-acetic acid tert-butyl or benzyl acetate bromide.
Further preferably say, above-mentioned (1) step is：First 4- amino -3-hydroxybutyrate and the alcohol of 5～20 times of weight are mixed
Close, be subsequently adding acylating agent or catalyst and react 1～5 hour at 0～60 DEG C, 4- amino -3-hydroxybutyrate and acylating agent or
Catalyst molar ratio is 1：1.5～1.65；The alcoholic solution containing intermediate compound I is obtained, then from the alcoholic solution containing intermediate compound I
Collect intermediate compound I；The alcohol is methyl alcohol, ethanol, normal propyl alcohol, isopropanol, n-butanol, the tert-butyl alcohol, cyclohexanol or cyclopentanol；Described
Acylating agent is concentrated hydrochloric acid, the concentrated sulfuric acid, thionyl chloride, POCl3, phosphorus pentachloride or oxalyl chloride；The catalyst be the concentrated sulfuric acid,
Loprazolam, p-methyl benzenesulfonic acid or trifluoroacetic acid.
Specifically, above-mentioned (2) step：It is the intermediate compound I that will be obtained from step (1), in 4- amino -3-hydroxybutyrate
React 5～10 hours in the presence of base catalyst with halogenated acetic acids ester in the solvent of 10-15 times of weight, reaction temperature is 0～60
DEG C, then collect and obtain intermediate II；The solvent select methyl alcohol, ethanol, isopropanol, tetrahydrofuran, in DMF, DMSO one
Plant or multiple combination；Described base catalyst is preferably pyridine, triethylamine, lutidines, potassium carbonate or sodium acid carbonate；Middle
Body I with the mol ratio of halogenated acetic acids ester is：1:1～3, intermediate compound I with the mol ratio of the base catalyst is：1:2～3.
The present invention has the advantages that：
Oxiracetam synthetic route of the present invention is a synthetic route for being suitable to industrialized production, is especially advantageous for dividing for product
From purifying, synthetic route of the present invention can at least obtain (the S)-Oxiracetam of more than 20% more satisfactory yield or DL body Aura west
Smooth product, opens a new Oxiracetam synthetic route.Meanwhile, synthetic route of the present invention is by further optimal control bar
Final (S)-Oxiracetam that part is obtained or the purity of DL body Oxiracetam product and optical purity all up to more than 99.9%,
Total recovery reaches 48.2%.Meanwhile, using the present invention (S)-Oxiracetam or DL body Oxiracetam synthetic method with existing
Technology compare, raw material is cheap and easy to get, purify without the need for column chromatography, low cost, easy to operate, better quality.The present invention is opened
One new Oxiracetam synthetic route.
Specific embodiment
The present invention is specifically described below by embodiment, it is necessary to it is pointed out here that, following examples are only used
In being further detailed to the present invention, it is impossible to be interpreted as limiting the scope of the invention, being skilled in technique of the field
Personnel can make some nonessential modifications and adaptations according to foregoing invention content to the present invention.
Embodiment 1
A kind of synthetic method of (S)-Oxiracetam, it is carried out as follows,
The preparation of (l) intermediate compound I：
Raw material S-4- amino -3-hydroxybutyrate 50g is taken, is added in a single neck bottle, adds methyl alcohol 50ml, stirring, ice-water bath
Cooling, is slowly dropped into concentrated hydrochloric acid 150ml, and keeping temperature is less than 40 DEG C, and solid first has a course of dissolution, then separates out again,
When drop makes a concentrated effort to finish, solid dissolves again, eventually forms a faint yellow supernatant liquid.Continue stirring 3 hours, raw material base is shown in by point plate
This reaction completely, stops reaction, and directly concentration removes solvent and obtains pale yellow oil, and curing at low temperatures obtains intermediate compound I.Through core
Magnetic testi, intermediate compound I is：1H-NMR(300MHz,D2O):δ2.76-2.67(AB system,m,2H,),3.31-3.23(AB
system,m,2H),3.75(s,3H),4.40(m,1H),4.70(bs,3H).13C-NMR(50MHz,D2O):δ43.7(C-2),
48.4 (C-4), 57.0 (OCH), 68.9 (C-3), 177.5 (C-I). intermediate compound I is：
R1 is methyl.
(2) preparation of intermediate II
The intermediate compound I that step (1) is obtained is dissolved in the methyl alcohol of 500ml, is cooled to 0 DEG C of outer temperature, adds potassium carbonate
173g (3eq), has a large amount of solids to generate, stirs five minutes, starts to drip bromoacetate 90ml (2eq), and dropping process is put
Thermal phenomenon, continues stirring 2 hours after completion of dropping, point plate is shown in that raw material reaction completely, stops reaction, adds EA (ethyl acetate)
500ml, water 300ml, solid are completely dissolved, and water layer solid sodium chloride saturation separates organic layer, and water layer is extracted with EA200ml
Take twice, merge organic layer, organic layer is washed three times with the hydrochloric acid 200ml of 2M, merge hydrochloric acid water phase, organic phase is discarded, and water is successive
Continuous sodium acid carbonate adjusts pH to 8, and solid sodium chloride saturation, EA 300ml are extracted three times, merge organic phase, and anhydrous magnesium sulfate is done
Dry, concentrate removing solvent and pale yellow oil is obtained, curing at low temperatures obtains intermediate II.Detect through nuclear-magnetism, intermediate II：
1H-NMR(300MHz,D2O):δ1.3(t,3H),2.28-2.53(m,2H),2.58-2.83(m,2H)3.51(s,2H),3.67
(s, 3H), 4.09-4.12 (m, 3H). intermediate II is：
R1 is methyl, and R2 is ethyl.
(3) preparation of intermediate III
The intermediate II that step (2) is obtained 500ml ethanol dissolves, and is warming up to 75 DEG C, flows back 8 hours, obtains one red
Brown solution, point plate are shown in that raw material reaction is complete.Stop reaction, concentrate and ethanol is removed, EA (ethyl acetate) dissolving is added, is crossed and filters
Desalt, activated carbon decolorizing, concentrate remove yellow oil obtains intermediate III.Detect through nuclear-magnetism, intermediate III is：1H-NMR
(300MHz,CDCl3)δ1.280(t,3H),2.38(dd,1H),2.69(dd,1H),3.34(dd,1H),3.77(dd,lH),
3.93 (d, lH), 4.18 (d, 1H), 4.19 (q, 2H), 4.30 (bs, 1H), 4.50 (m, 1H). intermediate III：
R2 is ethyl.
(4) preparation of (S)-Oxiracetam
The intermediate III that step (3) is obtained adds concentrated ammonia liquor 200ml, is stirred at room temperature 18 hours, and raw material reaction is shown in by point plate
Completely, stop reaction, concentrate and eliminating water and ammonia is removed, yellow oil is obtained, acetone solution grease is added, add a small amount of crystal seed
Stirring, precipitation solid, a small amount of acetone rinsing bottle wall, -10 DEG C crystallize 5 hours, are filtrated to get off-white color crude product 36g.Purity
99.3%, isomer proportion 0.2%.By the dissolving crude product in the water of 100ml, heating makes its dissolving, and activated carbon decolorizing half is little
When, it is filtered to remove activated carbon, crystallisation by cooling, 5 DEG C stand overnight, and next day filters to obtain white solid 32g, purity 99.9%, isomery
Body ratio 0.1%, yield are 48.2%, detect through nuclear-magnetism, levo-oxiracetam：1H-NMR(300MHz,DMSO-d6)δ2.10
(d,1H),2.57(dd,1H),3.69(d,1H),3.88(d,1H),4.10(d,1H),4.31(m,1H),5.25(s,1H),
7.13 (s, 1H), 7.33 (s, 1H). optical value：-37.3.
(S)-Oxiracetam is that structural formula is as follows：
Embodiment 2
1st, a kind of synthetic method of (S)-Oxiracetam, as follows：
(1) by S-4- amino -3-hydroxybutyrate and the ethanol for accounting for its 18 times of weight, stirring, esterification 5 is reacted at 60 DEG C
Hour or so, raw material fundamental reaction completely, stops reaction, directly concentrates and removes solvent, and curing at low temperatures obtains intermediate compound I；With
When above solvent additionally use methyl alcohol, normal propyl alcohol, isopropanol, n-butanol, the tert-butyl alcohol, cyclohexanol or cyclopentanol etc. to prepare centre
Body I, most after detect that obtained intermediate compound I is through nuclear-magnetism：1H-NMR(300MHz,D2O):δ 1.30 (m, 3H), 2.76-2.67
(AB system,m,2H,),3.31-3.23(AB system,m,2H),4.12(m,2H),4.40(m,1H),4.70(bs,
3H)..
(2) intermediate compound I that will be obtained from step (1), in the ethanol of 15 times of weight of S-4- amino -3-hydroxybutyrate,
Stirring cooling, drips bromoacetic acid 60 DEG C of N-butyl condensation reaction 10 hours, and the intermediate compound I with the mol ratio of halogenated acetic acids ester is
1:1.5, then collect and intermediate II is obtained, while above solvent additionally uses methyl alcohol, isopropanol, tetrahydrofuran, DMF or DMSO
Etc. preparing intermediate II, most after detect through nuclear-magnetism, obtained intermediate II is：1H-NMR(300MHz,D2O):δ0.96
(t,3H),1.30-1.33(m,5H),1.57(m,2H),2.28-2.53(m,2H),2.58-2.83(m,2H)3.51(s,2H),
4.08-4.12(m,5H)..
(3) intermediate II for obtaining step (2), is dissolved in ethyl acetate, the intermediate II and ethyl acetate
Mol ratio is 1：12, being warming up at 85 DEG C carries out ring closure reaction 6.5 hours, obtains the solution containing intermediate III, then from containing
Have to collect in the solution of intermediate III and intermediate III is obtained, described solvent is additionally used as ethanol, the tert-butyl alcohol, toluene, diformazan
Benzene, water, butyl acetate or ethyl butyrate, most after detect that obtained intermediate III is through nuclear-magnetism：1H-NMR(300MHz,
CDCl3)δ0.96(t,3H)1.33(m,2H),1.57(m,2H)2.38(dd,1H),2.69(dd,1H),3.34(dd,1H),
3.77(dd,lH),3.93(d,lH),4.18(d,1H),4.19(q,2H),4.30(bs,1H),4.50(m,1H)..
(4) intermediate III for obtaining step (3) is added in concentrated ammonia liquor, and being stirred at room temperature carries out ammonolysis reaction 15 hours, institute
State intermediate III：The mol ratio of ammonia is intermediate III：Ammonia=1：13, in terms of the ammonia in ammonia methanol solution；Reaction is concentrated completely
Eliminating water and ammonia is removed, is purified using acetone, crystallization obtains product (S)-Oxiracetam crude product.By dissolving crude product in water, heat molten
Solution, activated carbon decolorizing, it is filtered to remove activated carbon, reduced pressure concentration eliminating water, stop when surplus water is for adding 2～3 times of products weight
Only concentrate, 0～5 DEG C of sub-cooled crystallization, obtain product (S)-Oxiracetam.It is 80.4% that HPLC determines its purity, calculates and must receive
Rate is 20%, detects through nuclear-magnetism, and gained levo-oxiracetam is：1H-NMR(300MHz,DMSO-d6)δ2.10(d,1H),2.57
(dd,1H),3.69(d,1H),3.88(d,1H),4.10(d,1H),4.31(m,1H),5.25(s,1H),7.13(s,1H),
7.33 (s, 1H). optical value：-37.2.
Embodiment 3-12：With respect to the embodiment that embodiment 2 optimizes further for the present invention, by the step of table 1 below and
Parameter is carried out, other same as Example 1.
Table 1
Detect through nuclear-magnetism, intermediate prepared by embodiment 3-12 is as shown in table 2 with levo-oxiracetam：
As obtained in above example 3-12, levo-oxiracetam determines its purity in 99.5-99.9% through HPLC, calculates
Yield is in 35-45%.
Embodiment 13
1st, a kind of synthetic method of DL body Oxiracetam, as follows：
(1) by 4- amino -3-hydroxybutyrate and the ethanol for accounting for its 18 times of weight, stirring, little in 60 DEG C of reaction esterifications 5
When or so, raw material fundamental reaction completely, stops reaction, directly concentrates and removes solvent, and curing at low temperatures obtains intermediate compound I；Simultaneously
Above solvent additionally uses methyl alcohol, normal propyl alcohol, isopropanol, n-butanol, the tert-butyl alcohol, cyclohexanol or cyclopentanol etc. to prepare intermediate
I, most after detect that obtained intermediate compound I is through nuclear-magnetism：1H-NMR(300MHz,D2O):δ 1.28 (m, 3H), 2.75-2.66
(AB system,m,2H,),3.30-3.22(AB system,m,2H),4.09(m,2H),4.39(m,1H),4.72(bs,
3H)..
(2) intermediate compound I that will be obtained from step (1), in the ethanol of 15 times of weight of 4- amino -3-hydroxybutyrate, stirs
Cooling is mixed, bromoacetic acid 60 DEG C of N-butyl condensation reaction 10 hours is dripped, the intermediate compound I is 1 with the mol ratio of halogenated acetic acids ester:
1.5, then collect and intermediate II is obtained, while above solvent additionally uses methyl alcohol, isopropanol, tetrahydrofuran, DMF or DMSO etc.
To prepare intermediate II, most after detect that obtained intermediate II is through nuclear-magnetism：1H-NMR(300MHz,D2O):δ0.95(t,
3H),1.31-1.34(m,5H),1.55(m,2H),2.29-2.54(m,2H),2.56-2.81(m,2H)3.50(s,2H),
4.05-4.10(m,5H)..
(3) intermediate II for obtaining step (2), is dissolved in ethyl acetate, the intermediate II and ethyl acetate
Mol ratio is 1：12, being warming up at 85 DEG C carries out ring closure reaction 6.5 hours, obtains the solution containing intermediate III, then from containing
Have to collect in the solution of intermediate III and intermediate III is obtained, described solvent is additionally used as ethanol, the tert-butyl alcohol, toluene, diformazan
Benzene, water, butyl acetate or ethyl butyrate, most after detect that obtained intermediate III is through nuclear-magnetism：1H-NMR(300MHz,
CDCl3)δ0.94(t,3H)1.32(m,2H),1.55(m,2H)2.37(dd,1H),2.68(dd,1H),3.33(dd,1H),
3.77(dd,lH),3.92(d,lH),4.16(d,1H),4.18(q,2H),4.31(bs,1H),4.50(m,1H)..
(4) intermediate III for obtaining step (3) is added in concentrated ammonia liquor, and being stirred at room temperature carries out ammonolysis reaction 15 hours, institute
State intermediate III：The mol ratio of ammonia is intermediate III：Ammonia=1：13, in terms of the ammonia in ammonia methanol solution；Reaction is concentrated completely
Eliminating water and ammonia is removed, is purified using acetone, crystallization obtains product (S)-Oxiracetam crude product.By dissolving crude product in water, heat molten
Solution, activated carbon decolorizing, it is filtered to remove activated carbon, reduced pressure concentration eliminating water, stop when surplus water is for adding 2～3 times of products weight
Only concentrate, 0～5 DEG C of sub-cooled crystallization, obtain product DL body Oxiracetam.It is 82.1% that HPLC determines its purity, calculates
Yield is 19.5%, detects through nuclear-magnetism, and gained DL body Oxiracetam is：1H-NMR(300MHz,DMSO-d6)δ2.05(d,
1H),2.43(dd,1H),3.57(d,1H),3.78(d,1H),4.10(d,1H),4.35(m,1H),5.31(s,1H),7.23
(s,1H),7.43(s,1H).
Claims (6)
1. a kind of synthetic method of (S)-Oxiracetam, it is characterised in that reaction expression is as follows：
Comprise the steps：
(1) with S-4- amino -3-hydroxybutyrate as initiation material, esterification is carried out with alcohol, obtain intermediate compound I；
(2) intermediate compound I and halogenated acetic acids ester are carried out condensation reaction, obtains intermediate II；
(3) intermediate II is carried out ring closure reaction and obtains intermediate III；
(4) intermediate III is carried out ammonolysis reaction, obtains target product (S)-Oxiracetam；
(1) step is first to mix S-4- amino -3-hydroxybutyrate with the alcohol of 5～20 times of weight, is subsequently adding acylating agent
Or catalyst is reacted 1～5 hour at 17～60 DEG C, S-4- amino -3-hydroxybutyrate is 1 with acylating agent or catalyst molar ratio
: 1.5～1.65；The alcoholic solution containing intermediate compound I is obtained, from the alcoholic solution containing intermediate compound I, then collects intermediate compound I；Institute
Alcohol is stated for methyl alcohol, ethanol, normal propyl alcohol, isopropanol, n-butanol, the tert-butyl alcohol, cyclohexanol or cyclopentanol；The acylating agent is dense salt
Acid, the concentrated sulfuric acid, thionyl chloride, POCl3, phosphorus pentachloride or oxalyl chloride；The catalyst be the concentrated sulfuric acid, Loprazolam, to first
Benzene sulfonic acid or trifluoroacetic acid；
(2) step is the intermediate compound I that will be obtained from step (1), in the 10-15 times of weight of S-4- amino -3-hydroxybutyrate
Solvent in react 5～10 hours in the presence of base catalyst with halogenated acetic acids ester, reaction temperature be 20～55 DEG C, then collect
Obtain intermediate II；The solvent select methyl alcohol, ethanol, isopropanol, tetrahydrofuran, one or more group in DMF, DMS0
Close；Described base catalyst is pyridine, triethylamine, lutidines, potassium carbonate or sodium acid carbonate；Intermediate compound I and halogenated acetic acids
The mol ratio of ester is：1: 1～3, intermediate compound I with the mol ratio of the base catalyst is：1: 2～3；Described halogenated acetic acids ester is
Bromoacetate, ethyl chloroacetate, bromoacetic acid N-butyl, bromide isobutyl acetate, bromo-acetic acid tert-butyl or benzyl acetate bromide；
Step (3) are the intermediate II for obtaining step (2), carry out ring closure reaction under the conditions of 87～120 DEG C in a solvent,
Time is 3～8 hours, obtains the solution containing intermediate III, then collects from the solution containing intermediate III in obtaining
Mesosome III；Described solvent may be selected：Ethanol, the tert-butyl alcohol, toluene, dimethylbenzene, water, ethyl acetate, butyl acetate or butyric acid second
Ester；
Step (4)：It is the intermediate III that step (3) is obtained, reacts 4～16 hours with concentrated ammonia liquor at 20～30 DEG C,
Then target product (S)-Oxiracetam is collected from product；The intermediate III：The mol ratio of ammonia is intermediate III：
Ammonia=1: 12～15, in terms of the ammonia in ammonia methanol solution.
2. the synthetic method of as claimed in claim 1 (S)-Oxiracetam, it is characterised in that：By (4) step gained product
It is dissolved in the water, heating for dissolving, activated carbon decolorizing, activated carbon is filtered to remove, reduced pressure concentration eliminating water, when surplus water is produced for adding
Stop concentrating during 2～3 times of thing weight, 0～5 DEG C of sub-cooled crystallization, obtain product (S)-Oxiracetam.
3. a kind of synthetic method of Oxiracetam, it is characterised in that comprise the steps：
(1) with 4- amino -3-hydroxybutyrate as initiation material, esterification is carried out with alcohol, obtain intermediate compound I；
(2) intermediate compound I and halogenated acetic acids ester are carried out condensation reaction, obtains intermediate II；
(3) intermediate II is carried out ring closure reaction and obtains intermediate III；
(4) intermediate III is carried out ammonolysis reaction, obtains target product Oxiracetam；
(1) step is first to mix 4- amino -3-hydroxybutyrate with the alcohol of 5～20 times of weight, be subsequently adding acylating agent or
Catalyst is reacted 1～5 hour at 17～60 DEG C, and 4- amino -3-hydroxybutyrate is 1: 1.5 with acylating agent or catalyst molar ratio
～1.65；The alcoholic solution containing intermediate compound I is obtained, from the alcoholic solution containing intermediate compound I, then collects intermediate compound I；The acyl
Agent is concentrated hydrochloric acid, the concentrated sulfuric acid, thionyl chloride, POCl3, phosphorus pentachloride or oxalyl chloride；The catalyst is the concentrated sulfuric acid, first
Alkyl sulfonic acid, p-methyl benzenesulfonic acid or trifluoroacetic acid；
(2) step is the intermediate compound I that will be obtained from step (1), in the 10-15 times of weight of 4- amino -3-hydroxybutyrate
React 5～10 hours in the presence of base catalyst with halogenated acetic acids ester in solvent, reaction temperature is 20～55 DEG C, then collect and obtain
Obtain intermediate II；The solvent selects methyl alcohol, ethanol, isopropanol, tetrahydrofuran, one or more combination in DMF, DMSO；
Described base catalyst is pyridine, triethylamine, lutidines, potassium carbonate or sodium acid carbonate；Intermediate compound I and halogenated acetic acids ester
Mol ratio is：1: 1～3, intermediate compound I with the mol ratio of the base catalyst is：1: 2～3；The halogenated acetic acids ester adopts bromine second
Acetoacetic ester, ethyl chloroacetate, bromoacetic acid N-butyl, bromide isobutyl acetate, bromo-acetic acid tert-butyl or benzyl acetate bromide；
Step (3) are the intermediate II for obtaining step (2), carry out ring closure reaction under the conditions of 87～120 DEG C in a solvent,
Time is 3～8 hours, obtains the solution containing intermediate III, then collects from the solution containing intermediate III in obtaining
Mesosome III；Described solvent may be selected：Ethanol, the tert-butyl alcohol, toluene, dimethylbenzene, water, ethyl acetate, butyl acetate or butyric acid second
Ester.
4. the synthetic method of Oxiracetam as claimed in claim 3, it is characterised in that
The alcohol of (1) step is methyl alcohol, ethanol, normal propyl alcohol, isopropanol, the tert-butyl alcohol, cyclohexanol or cyclopentanol；The halo second
Acid esters adopts bromoacetate, ethyl chloroacetate or benzyl acetate bromide.
5. the synthetic method of Oxiracetam as claimed in claim 3, it is characterised in that step (4) are to obtain step (3)
Intermediate III, react with concentrated ammonia liquor at 20～30 DEG C 4～16 hours, from product, then collect target product difficult to understand
La Xitan；The intermediate III：The mol ratio of ammonia is intermediate III：Ammonia=1: 12～15, with the ammonia in ammonia methanol solution
Meter.
6. the synthetic method of Oxiracetam as claimed in claim 5, it is characterised in that：(4) step gained product is dissolved
Yu Shuizhong, heating for dissolving, activated carbon decolorizing, activated carbon is filtered to remove, reduced pressure concentration eliminating water, when surplus water is for adding product weight
Stop concentrating when measuring 2～3 times, 0～5 DEG C of sub-cooled crystallization, obtain product Oxiracetam.
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| CN107021902A (en) * | 2016-01-29 | 2017-08-08 | 重庆润泽医药有限公司 | A kind of levo-oxiracetam crystal formation I preparation method |
| CN107021907A (en) * | 2016-01-29 | 2017-08-08 | 重庆润泽医药有限公司 | Levo-oxiracetam crystal formation II preparation method |
| CN107021909A (en) * | 2016-01-29 | 2017-08-08 | 重庆润泽医药有限公司 | A kind of levo-oxiracetam crystal formation II preparation method |
| CN107021910A (en) * | 2016-01-29 | 2017-08-08 | 重庆润泽医药有限公司 | The method for preparing S-oxiracetam crystal formation II |
| CN107021908A (en) * | 2016-01-29 | 2017-08-08 | 重庆润泽医药有限公司 | The method for preparing levo-oxiracetam crystal formation II |
| CN107021913A (en) * | 2016-01-29 | 2017-08-08 | 重庆润泽医药有限公司 | A kind of method for preparing levo-oxiracetam crystal formation I |
| CN107021897A (en) * | 2016-01-29 | 2017-08-08 | 重庆润泽医药有限公司 | A kind of method for preparing levo-oxiracetam crystal formation II |
| CN107021896A (en) * | 2016-01-29 | 2017-08-08 | 重庆润泽医药有限公司 | A kind of levo-oxiracetam crystal formation II preparation method |
| CN107021899A (en) * | 2016-01-29 | 2017-08-08 | 重庆润泽医药有限公司 | A kind of method for preparing levo-oxiracetam crystal formation II |
| CN107021914A (en) * | 2016-01-29 | 2017-08-08 | 重庆润泽医药有限公司 | Levo-oxiracetam crystal formation II preparation method |
| CN107021905A (en) * | 2016-01-29 | 2017-08-08 | 重庆润泽医药有限公司 | The method for preparing levo-oxiracetam crystal formation II |
| CN107021900A (en) * | 2016-01-29 | 2017-08-08 | 重庆润泽医药有限公司 | A kind of (S)-Oxiracetam crystal form II preparation method |
| CN107021904A (en) * | 2016-01-29 | 2017-08-08 | 重庆润泽医药有限公司 | The method for preparing levo-oxiracetam crystal formation II |
| CN107021903A (en) * | 2016-01-29 | 2017-08-08 | 重庆润泽医药有限公司 | A kind of levo-oxiracetam crystal formation I preparation method |
| CN106496089B (en) * | 2016-02-05 | 2019-05-21 | 华润双鹤药业股份有限公司 | A method of preparing Oxiracetam |
| CN108659004B (en) * | 2018-07-12 | 2020-11-10 | 福安药业集团重庆博圣制药有限公司 | Preparation method of oxiracetam isomer |
| US11785966B2 (en) | 2019-03-06 | 2023-10-17 | Anipha Technologies Pty Ltd | Use of gamma-quaternary ammonium butyrate compound in preparation of an animal feed additive |
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