CN106631961A - Synthetic method of oxiracetam - Google Patents
Synthetic method of oxiracetam Download PDFInfo
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- CN106631961A CN106631961A CN201610854853.0A CN201610854853A CN106631961A CN 106631961 A CN106631961 A CN 106631961A CN 201610854853 A CN201610854853 A CN 201610854853A CN 106631961 A CN106631961 A CN 106631961A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention discloses a synthetic method of (S)-oxiracetam. The synthetic method includes the steps of (1), taking S-4-amio-3-hydroxybutyrate as an initial raw material, and performing esterification reaction with alcohol, and acquiring a midbody I; (2), performing condensation reaction on midbody I and halogenated acetate to obtain a midbody II; (3), performing the ring closing reaction on the midbody II and acquiring a midbody III; (4), performing the ammonolysis reaction on the midbody III to obtain a target product (S)-oxiracetam. The synthetic route of oxiracetam can at least acquire over 20% of (S)-oxiracetam with ideal yield, and opens 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
It, than the cereboactive drug that Qie Mu company synthesized first in 1974, is by two kinds of isomeries that Oxiracetam is by Italian SmithKline
The raceme of body (S)-Oxiracetam ((S)-oxiracetam) and (R)-Oxiracetam ((R)-oxiracetam) composition.(S)-
Oxiracetam is a single enantiomer of Oxiracetam, and chemistry is entitled：(S) oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2.
Nootropic Oxiracetam is a kind of 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 fourths
Acid is initiation material, and Jing sillylation reagents protection hydroxyl, the product after cyclization reacts with halogenated acetic acids ethyl ester, product
Jing Deprotections, ammonolysis finally obtain target compound.This kind of preparation method is not suitable for industrial-scale production, because it
Have disadvantages that, such as carrying out protection to hydroxyl using protection group can increase reactions steps, waste raw material, it is time-consuming longer, increase into
This, reduces total recovery.In addition, in this course of reaction, needing to carry out column chromatography purifying to intermediate, next step can be just carried out
Reaction.These shortcomings are all very unfavorable for industrial-scale production.
Document：Tetrahedron:Asymmetry 1992,3 (11) reports a kind of method of the synthesis compound；With
Malic acid and glycine methyl ester are initiation material, and hydroxyl, Deprotection, ammonia are removed in chloroacetic chloride protection hydroxyl, chosen property reduction
Solution, obtains target compound.In this approach, need to carry out a selective reduction and cause the various accessory substances of generation, 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-hydroxyls ethyl butyrate reacts with glycine amide
Target compound is obtained, or target compound is obtained with glycine ethyl ester reaction, then Jing ammonolysis.Wherein chloro- 3- hydroxyls of (S) -4-
Base butyrate reacts in the basic conditions that to obtain final products Oxiracetam be by disposably plus alkali is controlling with sweet amine amide
The alkalescence of reactant liquor, but because Oxiracetam is more easily damaged in strong base solution, so directly affects the pure of Oxiracetam
Degree and yield；Adopt silica gel column chromatography method in purifying final products Oxiracetam in addition, the eluent for using is organic mixed
Bonding solvent, quantity of solvent is big, is 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 equally added dropwise under hot conditions and carried out by the way of highly basic
Condensation, can cause condensation yield relatively low while condensation with various side reactions such as S-4- halogen -3-hydroxybutyrate ester hydrolysis,
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 is low, it is difficult to industrialize.
The 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, obtains intermediate compound I；
(2) intermediate compound I and halogenated acetic acids ester are carried out into condensation reaction, obtains intermediate II；
(3) intermediate II is carried out into ring closure reaction and obtains intermediate III；
(4) intermediate III is carried out into ammonolysis reaction, obtains target product (S)-Oxiracetam.
Reaction expression is as follows：
Inventor studies through long-term experiment, has attempted many new synthesis routes and has been difficult to obtain (S)-Oxiracetam, most
Above synthetic route is pressed eventually, and the cooperation of each reaction type and sequencing is so as to obtaining more than 20% more satisfactory yield by more than
(S)-Oxiracetam product, open a new Oxiracetam synthetic route.
In order that impurity is more easily separated, operating procedure simple, so as to the work for obtaining high-purity product, promoting 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 further improve reactivity, so as to further improve reaction yield, 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 reacts 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, intermediate compound I is then collected from the alcoholic solution containing intermediate compound I.
Above-mentioned S-4- amino -3-hydroxybutyrate, alcohol and acylating reagent is commercially available prod.
Above-mentioned (2) step, is the intermediate compound I that will be obtained from step (1), in a solvent with halogenated acetic acids ester specifically
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
Without particular/special requirement, one or more combination in prioritizing selection methyl alcohol, ethanol, isopropanol, tetrahydrofuran, DMF, DMSO；It is 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 is with the mol ratio of halogenated acetic acids ester：1:1～3,
Intermediate compound I is with the mol ratio of the base catalyst：1:2～3.
Most specifically say, above-mentioned (2) step, be the intermediate compound I that will be obtained from step (1), in S-4- amino -3- hydroxyl fourths
React in the presence of base catalyst 5～10 hours 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 without 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 is with the mol ratio of halogenated acetic acids ester：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, the 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.
The formula of intermediate III 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, the intermediate III that step (3) is obtained reacts at 20～30 DEG C with concentrated ammonia liquor
4～16 hours, target product (S)-Oxiracetam is then collected from product.
In order to further improve reactivity 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；What described concentrated ammonia liquor was known in the art, its solution
Concentrations by weight be 25～28% or so.
The method that target product (S)-Oxiracetam is collected from the product of above-mentioned steps (4), preferably by following step
Suddenly：Product is dissolved in the water, heating for dissolving, activated carbon decolorizing is filtered to remove activated carbon, reduced pressure concentration eliminating water, when surplus
Remaining water stop during 2～3 times of products weight concentration to add, 0～5 DEG C of sub-cooled crystallization, obtains to obtain product (S)-Aura west
It is 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, obtains intermediate compound I；
(2) intermediate compound I and halogenated acetic acids ester are carried out into condensation reaction, obtains intermediate II；
(3) intermediate II is carried out into ring closure reaction and obtains intermediate III；
(4) intermediate III is carried out into ammonolysis reaction, obtains target product Oxiracetam.
Inventor has attempted many new synthesis routes and has been difficult to obtain Oxiracetam, finally presses above synthetic route, passes through
More than each reaction type and sequencing cooperation so as to obtain the Oxiracetam product of more than 20% more satisfactory yield, open
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；It is 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 in the presence of base catalyst 5～10 hours 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 selects in methyl alcohol, ethanol, isopropanol, tetrahydrofuran, DMF, DMSO
Plant or multiple combination；Described base catalyst is preferably pyridine, triethylamine, lutidines, potassium carbonate or sodium acid carbonate；It is middle
Body I is with the mol ratio of halogenated acetic acids ester：1:1～3, intermediate compound I is with the mol ratio of the base catalyst：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 or the purity and optical purity of DL body Oxiracetam product reachable more than 99.9% that part is obtained,
Total recovery reaches 48.2%.Meanwhile, using (S)-Oxiracetam of the invention or DL body Oxiracetam synthetic method with it is 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, the field is skilled in technique
Personnel can make some nonessential modifications and adaptations to the present invention according to foregoing invention content.
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, in adding a single neck bottle, methyl alcohol 50ml, stirring, ice-water bath is added
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,
Solid dissolves again when drop makes a concentrated effort to finish, and eventually forms a faint yellow supernatant liquid.Continue to stir 3 hours, point plate is shown in raw material base
This reaction completely, stops reaction, and directly concentration removes solvent and obtains pale yellow oil, and curing at low temperatures obtains intermediate compound I.Jing cores
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 first
Base.
(2) preparation of intermediate II
The intermediate compound I that step (1) is obtained is dissolved in the methyl alcohol of 500ml, 0 DEG C of outer temperature is cooled to, potassium carbonate is added
173g (3eq), has a large amount of solids to generate, and stirs five minutes, starts that bromoacetate 90ml (2eq) is added dropwise, and dropwise addition process is put
Thermal phenomenon, continues to stir 2 hours after completion of dropping, and point plate is shown in that raw material reaction completely, stops reaction, adds EA (ethyl acetate)
500ml, water 300ml, solid is completely dissolved, and by 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, merges organic phase, and anhydrous magnesium sulfate is done
Dry, concentration removes solvent and obtains pale yellow oil, and curing at low temperatures obtains intermediate II.The detection of Jing nuclear-magnetisms, 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 is shown in that raw material reaction is complete.Stop reaction, concentration removes ethanol, add EA (ethyl acetate) dissolvings, cross and filter
Desalt, activated carbon decolorizing, concentration remove yellow oil obtains intermediate III.Jing nuclear-magnetisms detect that 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 point plate is shown in raw material reaction
Completely, reaction is stopped, eliminating water and ammonia are removed in concentration, obtain yellow oil, add acetone solution grease, 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 dissolves it, 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 is that 48.2%, Jing nuclear-magnetisms are detected, 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 reacts esterification 5 at 60 DEG C
Hour or so, raw material fundamental reaction completely, stops reaction, and directly concentration removes solvent, and curing at low temperatures obtains intermediate compound I；Together
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 the detection of Jing nuclear-magnetisms, obtained intermediate compound I is：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, is added dropwise bromoacetic acid 60 DEG C of N-butyl condensation reaction 10 hours, and the intermediate compound I is with the mol ratio of halogenated acetic acids ester
1:1.5, then collect and obtain intermediate II, while above solvent additionally uses methyl alcohol, isopropanol, tetrahydrofuran, DMF or DMSO
Etc. preparing intermediate II, most after the detection of Jing nuclear-magnetisms, 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), in being dissolved in ethyl acetate, the intermediate II and ethyl acetate
Mol ratio is 1：12, ring closure reaction is carried out at being warming up to 85 DEG C 6.5 hours, the solution containing intermediate III is obtained, then from containing
Have to be collected in the solution of intermediate III and obtain intermediate III, described solvent is additionally used as ethanol, the tert-butyl alcohol, toluene, diformazan
Benzene, water, butyl acetate or ethyl butyrate, most after the detection of Jing nuclear-magnetisms, obtained intermediate III is：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 are removed, is purified using acetone, crystallization obtains product (S)-Oxiracetam crude product.By dissolving crude product in water, plus thermosol
Solution, activated carbon decolorizing is filtered to remove activated carbon, reduced pressure concentration eliminating water, stops when surplus water is to add 2～3 times of products weight
Only concentrate, 0～5 DEG C of sub-cooled crystallization obtains product (S)-Oxiracetam.It is 80.4% that HPLC determines its purity, and calculating to receive
Rate is the detection of 20%, Jing nuclear-magnetisms, 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：Relative to embodiment 2 for the further optimization of the present invention embodiment, by the step of table 1 below and
Parameter is carried out, other same as Example 1.
Table 1
Jing nuclear-magnetisms detect that intermediate prepared by embodiment 3-12 is as shown in table 2 with levo-oxiracetam：
The HPLC of the levo-oxiracetam Jing as obtained in above example 3-12 determine its purity in 99.5-99.9%, calculate
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 reacts esterification 5 little at 60 DEG C
When or so, raw material fundamental reaction completely, stops reaction, and directly concentration 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 the detection of Jing nuclear-magnetisms, obtained intermediate compound I is：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 added dropwise, the intermediate compound I is 1 with the mol ratio of halogenated acetic acids ester:
1.5, then collect and obtain intermediate II, while above solvent additionally uses methyl alcohol, isopropanol, tetrahydrofuran, DMF or DMSO etc.
To prepare intermediate II, most after the detection of Jing nuclear-magnetisms, obtained intermediate II is：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), in being dissolved in ethyl acetate, the intermediate II and ethyl acetate
Mol ratio is 1：12, ring closure reaction is carried out at being warming up to 85 DEG C 6.5 hours, the solution containing intermediate III is obtained, then from containing
Have to be collected in the solution of intermediate III and obtain intermediate III, described solvent is additionally used as ethanol, the tert-butyl alcohol, toluene, diformazan
Benzene, water, butyl acetate or ethyl butyrate, most after the detection of Jing nuclear-magnetisms, obtained intermediate III is：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 are removed, is purified using acetone, crystallization obtains product (S)-Oxiracetam crude product.By dissolving crude product in water, plus thermosol
Solution, activated carbon decolorizing is filtered to remove activated carbon, reduced pressure concentration eliminating water, stops when surplus water is to add 2～3 times of products weight
Only concentrate, 0～5 DEG C of sub-cooled crystallization obtains product DL body Oxiracetam.It is 82.1% that HPLC determines its purity, is calculated
Yield is the detection of 19.5%, Jing nuclear-magnetisms, 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 (8)
1. a kind of synthetic method of (S)-Oxiracetam, it is characterised in that reaction expression is as follows：
Wherein R1For methyl, ethyl, n-propyl, isopropyl, normal-butyl, the tert-butyl group, isobutyl group, cyclopenta or cyclohexyl；The R2
For ethyl, n-propyl, isopropyl, normal-butyl, the tert-butyl group, isobutyl group, benzyl or cyclopenta；
Comprise the steps：
(1) with S-4- amino -3-hydroxybutyrate as initiation material, esterification is carried out with alcohol, obtains intermediate compound I；
(2) intermediate compound I and halogenated acetic acids ester are carried out into condensation reaction, obtains intermediate II；
(3) intermediate II is carried out into ring closure reaction and obtains intermediate III；
(4) intermediate III is carried out into ammonolysis reaction, obtains target product (S)-Oxiracetam；
(1) step is S-4- amino -3-hydroxybutyrate to be added in alcohol, also in the condition for instilling acylating agent or catalyst
Under, carry out esterification and obtain intermediate compound I；The acylating agent is the concentrated hydrochloric acid, concentrated sulfuric acid, thionyl chloride, POCl3, phosphoric
Phosphorus or oxalyl chloride；The catalyst is the concentrated sulfuric acid, Loprazolam, 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 S-4- amino -3-hydroxybutyrate
Solvent in react in the presence of base catalyst 5～10 hours with halogenated acetic acids ester, reaction temperature be 0～60 DEG C, then collect
Obtain intermediate II；The solvent selects one or more group in methyl alcohol, ethanol, isopropanol, tetrahydrofuran, DMF, DMSO
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 is with the mol ratio of the base catalyst：1:2～3；
The step (3) is the intermediate II for obtaining step (2), carries out ring closure reaction under the conditions of 50～130 DEG C in a solvent,
Time is 3～8 hours, obtains the solution containing intermediate III, then collects from the solution containing intermediate III and obtains centre
Body III；Described solvent may be selected：Ethanol, the tert-butyl alcohol, toluene, dimethylbenzene, water, ethyl acetate, butyl acetate or ethyl butyrate.
The step (4)：It is the intermediate III for obtaining step (3), reacts 6～18 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 as claimed in claim 1 synthetic method of (S)-Oxiracetam, it is characterised in that：The R1For methyl, ethyl, positive third
Base, isopropyl, normal-butyl, the tert-butyl group, isobutyl group or cyclohexyl；The R2For ethyl, isopropyl, normal-butyl, the tert-butyl group, isobutyl
Base or benzyl.
3. the as claimed in claim 1 synthetic method of (S)-Oxiracetam, it is characterised in that：Halo second in the step (2)
Acid esters is monobromo-acetic acid ester or chloracetic acid ester.
4. as described in any one of claim 1-3 (S)-Oxiracetam synthetic method, it is characterised in that：In the step (2)
Halogenated acetic acids ester adopt bromoacetate, ethyl chloroacetate, bromoacetic acid N-butyl, bromide isobutyl acetate, bromo-acetic acid tert-butyl
Or benzyl acetate bromide.
5. the as claimed in claim 1 synthetic method of (S)-Oxiracetam, it is characterised in that mainly carry out as follows：
(1), first S-4- amino -3-hydroxybutyrate mixed with the alcohol of 5～20 times of weight, acylating agent is subsequently adding or catalyst is existed
React 1～5 hour at 0～60 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, intermediate compound I is then collected from the alcoholic solution containing intermediate compound I；The alcohol be methyl alcohol,
Ethanol, normal propyl alcohol, isopropanol, n-butanol or the tert-butyl alcohol, 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；
(2), will from step (1) obtain intermediate compound I, in the solvent of the 10-15 times of weight of S-4- amino -3-hydroxybutyrate with
Halogenated acetic acids ester reacts 5～10 hours in the presence of base catalyst, and reaction temperature is 20～50 DEG C, then collects and obtains intermediate
II；The solvent selects one or more combination in methyl alcohol, ethanol, isopropanol, tetrahydrofuran, DMF, DMSO, described alkali
Catalyst is pyridine, triethylamine, lutidines, potassium carbonate or sodium acid carbonate, described halogenated acetic acids ester be bromoacetate,
Ethyl chloroacetate, bromoacetic acid N-butyl, bromide isobutyl acetate, bromo-acetic acid tert-butyl or benzyl acetate bromide；The intermediate compound I and halogen
It is for the mol ratio of acetic acid esters：1:1～3, intermediate compound I is with the mol ratio of the base catalyst：1:2～3；
(3) it is, the intermediate II that obtains step (2), carries out ring closure reaction under the conditions of 50～130 DEG C in a solvent, the time is 3
～8 hours, the solution containing intermediate III is obtained, then collect from the solution containing intermediate III and obtain intermediate III；Institute
The solvent stated be ethanol, the tert-butyl alcohol, toluene, dimethylbenzene, water, ethyl acetate, butyl acetate or ethyl butyrate, the intermediate II
It is 1 with the mol ratio of solvent：10～30；
(4), the intermediate III for obtaining step (3), reacts 6～18 hours at 20～30 DEG C with concentrated ammonia liquor, obtains reaction and produces
Thing (S)-Oxiracetam crude product；The intermediate III：The mol ratio of ammonia is intermediate III：Ammonia=1：12～15, with ammonia methyl alcohol
Ammonia meter in solution；
(5), (4) step gained product is dissolved in the water, heating for dissolving, activated carbon decolorizing is filtered to remove activated carbon, subtracts
Pressure concentration eliminating water, concentration is stopped when surplus water is to add 2～3 times of products weight, and 0～5 DEG C of sub-cooled crystallization is produced
Thing (S)-Oxiracetam.
6. 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, obtains intermediate compound I；
(2) intermediate compound I and halogenated acetic acids ester are carried out into condensation reaction, obtains intermediate II；
(3) intermediate II is carried out into ring closure reaction and obtains intermediate III；
(4) intermediate III is carried out into ammonolysis reaction, obtains target product Oxiracetam；
Alcohol in the step (1) is methyl alcohol, ethanol, normal propyl alcohol, isopropanol, n-butanol, the tert-butyl alcohol, cyclohexanol or cyclopentanol；
(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 in the presence of base catalyst 5～10 hours with halogenated acetic acids ester in solvent, reaction temperature is 20～50 DEG C, then collect and obtain
Obtain intermediate II；The solvent selects one or more combination in methyl alcohol, ethanol, isopropanol, tetrahydrofuran, 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 is with the mol ratio of the base catalyst：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；
The step (3) is the intermediate II for obtaining step (2), carries out ring closure reaction under the conditions of 60～120 DEG C in a solvent,
Time is 3～8 hours, obtains the solution containing intermediate III, then collects from the solution containing intermediate III and obtains centre
Body III；Described solvent may be selected：Ethanol, the tert-butyl alcohol, toluene, dimethylbenzene, water, ethyl acetate, butyl acetate or ethyl butyrate.
7. the synthetic method of Oxiracetam as claimed in claim 6, it is characterised in that：The step (4)：It is to obtain step (3)
The intermediate III for arriving, reacts 7～15 hours at 20～30 DEG C with concentrated ammonia liquor, target product is then collected from product difficult to understand
La Xitan；The intermediate III：The mol ratio of ammonia is intermediate III：Ammonia=1：12～15, in terms of the ammonia in ammonia methanol solution.
8. the synthetic method of Oxiracetam as claimed in claim 7, it is characterised in that：By the gained product dissolving of (4) step
Yu Shuizhong, heating for dissolving, activated carbon decolorizing is filtered to remove activated carbon, reduced pressure concentration eliminating water, when surplus water is addition product weight
Stop concentration when measuring 2～3 times, 0～5 DEG C of sub-cooled crystallization obtains 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| CN111601512B (en) | 2019-03-06 | 2023-11-17 | 彭险峰 | Application of gamma-quaternary ammonium butyrate compounds in preparation of animal feed additives |
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