CN106349143A - Synthetic method of oxiracetam - Google Patents
Synthetic method of oxiracetam Download PDFInfo
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- CN106349143A CN106349143A CN201610754462.1A CN201610754462A CN106349143A CN 106349143 A CN106349143 A CN 106349143A CN 201610754462 A CN201610754462 A CN 201610754462A CN 106349143 A CN106349143 A CN 106349143A
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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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- 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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Abstract
The synthetic method of a (s)- oxiracetam comprises the steps of: (1) Intermediate I is obtained by the esterification reaction between S-4-amino-3-hydroxybutyric acid as the starting material and alcohol; (2) The intermediate I and the halogenated acetate ester have a condensation reaction to obtain intermediate II; (3) The intermediate II is subjected to a ring-closing reaction to obtain the intermediate III; (4) The intermediate III is subjected to an amination reaction to obtain the target product (S)- oxiracetam. The oxiracetam synthesis route of the invention can at least obtain the (S)-oxiracetam product with a desired yield of more than 20%. The synthetic method of oxiracetam opens up a new synthesis route for the oxiracetam.
Description
The application is Application No. " 201310243165.7 ", invention 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 is the nootropics being synthesized first in 1974 than Qie Mu company by Italian SmithKline, is by two kinds of isomeries
The raceme that body (s)-oxiracetam ((s)-oxiracetam) and (r)-oxiracetam ((r)-oxiracetam) form.(s)-
Oxiracetam is a single enantiomer of oxiracetam, and chemistry is entitled: (s) -4- hydroxyl -2 oxo-1-pyrrolidine ethanamide.
Nootropics oxiracetam is a kind of hydroxy-amino-butyric acid of synthesis (gabob) derivant, and it is that one kind can promote to learn, and strengthens note
Recall power, the medicine for central nervous system of protection damaged nerve cell.
At present, the method for the synthesis (s) of document report-oxiracetam 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, 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 using protection group to hydroxyl can increase reactions steps, waste raw material, take longer, increase into
This, make total recovery reduce.In addition, in this course of reaction, needing to carry out column chromatography purification to intermediate, next step just can be carried out
Reaction.These shortcomings are all very unfavorable for industrial-scale production.
Document: tetrahedron:asymmetry 1992,3 (11) reports a kind of method synthesizing this compound；With
Malic acid and glycine methyl ester are initiation material, and chloroacetic chloride protects hydroxyl, chosen property reduction, removes hydroxyl, Deprotection, ammonia
Solution, obtains target compound.In this approach, need to carry out a selective reduction and cause the multiple by-products of generation, and
Each intermediate is required for column chromatography purification, just can carry out next step reaction.Such technique equally can not meet industrialization
The requirement of scale.
Technology disclosed in patent w02005/115978, wherein (s) -4- chloro-3-hydroxyl ethyl n-butyrate. and Aminoacetamide are reacted
Obtain target compound, or react with glycine ethyl ester, then obtain target compound through ammonolysis.Wherein (s) -4- chloro- 3- hydroxyl
Base butyrate and sweet amine amide react that to obtain final products oxiracetam be by disposably plus alkali controls in the basic conditions
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；In addition adopt silica gel column chromatography method in purification final products oxiracetam, the eluent of use 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 reports one kind to be carried out with glycine and s-4- halogen -3-hydroxybutyrate ester for raw material
Condensation, then carry out being esterified the synthetic route of ammonolysis, but the method is carried out by the way of Deca highly basic equally under the hot conditionss
Condensation, can lead to condensation yield relatively low with multiple side reactions such as s-4- halogen -3-hydroxybutyrate ester hydrolysis while condensation,
By-product is more, obtains end-product s- oxiracetam and cannot direct crystallization separate out under this purity, needs ion exchange resin
Chromatography remove impurity, high cost, purity low it is difficult to industrialization.
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, carry out esterification with alcohol, obtain intermediate i；
(2) intermediate i is carried out condensation reaction with halogenated acetic acids ester, obtain intermediate ii；
(3) intermediate ii is carried out ring closure reaction and obtain intermediate；
(4) intermediate is carried out ammonolysis reaction, obtain target product (s)-oxiracetam.
Reaction expression is as follows:
Inventor studies through long-term experiment, has attempted a lot of new synthesis routes and has all been difficult to obtain (s)-oxiracetam,
Press above synthetic route eventually, by the cooperation of each response type and sequencing above thus obtaining more than 20% more satisfactory yield
(s)-oxiracetam product, open a new oxiracetam synthetic route.
So that impurity is more easily separated, operating procedure simple, thus obtaining high-purity product, promoting the work of pharmaceutical production
Industry, also ensures reaction yield simultaneously, and the halogenated acetic acids ester in above-mentioned steps (2) preferably employs 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 thus improving reaction yield further, above-mentioned (1) is preferably a step:
S-4- amino -3-hydroxybutyrate is added in alcohol, also under conditions of instilling acylating agent or catalyst, is esterified
Reaction obtains intermediate i；The optional methanol of described alcohol, ethanol, normal propyl alcohol, isopropanol, n-butyl alcohol, the tert-butyl alcohol, Hexalin or ring penta
Alcohol, it is preferred to use methanol, ethanol, normal propyl alcohol or cyclopentanol；Described acylating agent is concentrated hydrochloric acid, concentrated sulphuric acid, thionyl chloride, trichlorine oxygen
Phosphorus, phosphorus pentachloride or oxalyl chloride；Described catalyst is concentrated sulphuric acid, Loprazolam, p-methyl benzenesulfonic acid or trifluoroacetic acid.
Intermediate i formula is as follows:
R1 is methyl, ethyl, n-pro-pyl, 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；Obtain the alcoholic solution containing intermediate i, from the alcoholic solution containing intermediate i, then collect intermediate i.
Above-mentioned s-4- amino -3-hydroxybutyrate, alcohol and acylating reagent are commercially available prod.
Above-mentioned (2) step, specifically, is the intermediate i that will obtain 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；Described solvent
No particular/special requirement, prioritizing selection methanol, ethanol, isopropanol, oxolane, one or more of dmf, dmso combination；Described
Base catalyst be preferably pyridine, triethylamine, lutidines, potassium carbonate or sodium bicarbonate.
In order to further improve reaction purity and yield, intermediate i with the mol ratio of halogenated acetic acids ester is: 1:1～3,
Intermediate i with the mol ratio of described base catalyst is: 1:2～3.
Most specifically say that above-mentioned (2) step is the intermediate i that will obtain from step (1), in s-4- amino -3- hydroxyl fourth
React in the presence of base catalyst 5～10 hours with halogenated acetic acids ester in the solvent of 10-15 times of weight of acid, reaction temperature is 0
～60 DEG C, then collect and obtain intermediate ii；Described solvent no particular/special requirement, prioritizing selection methanol, ethanol, isopropanol, tetrahydrochysene
Furan, one or more of dmf, dmso combination；Described base catalyst is preferably pyridine, triethylamine, lutidines, carbon
Sour potassium or sodium bicarbonate；Intermediate i with the mol ratio of halogenated acetic acids ester is: 1:1～3, and intermediate i is rubbed with described base catalyst
That ratio is: 1:2～3.
Intermediate ii formula is as follows:
R1 is methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, isobutyl group, cyclopenta or cyclohexyl etc.；
R2 is ethyl, n-pro-pyl, 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
Carry out ring closure reaction, the time is 3～8 hours, obtains the solution containing intermediate, then from the solution containing intermediate
Collection obtains intermediate；Described solvent may be selected: ethanol, the tert-butyl alcohol, toluene, dimethylbenzene, water, ethyl acetate, acetic acid fourth
Ester or ethyl n-butyrate., it is preferred to use ethanol, toluene or dimethylbenzene.
Intermediate formula is as follows:
R2 is ethyl, n-pro-pyl, 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 1:10～30 with the mol ratio of solvent.
Above-mentioned steps (4), specifically, intermediate that step (3) is obtained, is reacted with strong aqua ammonia at 20～30 DEG C
4～16 hours, from product, then collect target product (s)-oxiracetam.
In order to improve reactivity further thus improving overall yield of reaction, above-mentioned intermediate: during the mol ratio of ammonia is
Mesosome: ammonia=1:12～15, in terms of the ammonia in ammonia methanol solution；Described strong aqua ammonia is known in the art, its solution
Concentrations by weight be 25～28% about.
The method collecting target product (s)-oxiracetam from the product of above-mentioned steps (4), preferably presses following walking
Rapid: product is dissolved in the water, heating for dissolving, activated carbon decolorizing, it is filtered to remove activated carbon, concentrating under reduced pressure eliminating water, when surplus
Remaining water is to stop concentrating when adding 2～3 times of products weight, 0～5 DEG C of sub-cooled crystallization, obtains to obtain product (s)-Aura west
Smooth.
A kind of synthetic method of DL body oxiracetam is it is characterised in that comprise the steps:
(1) with 4- amino -3-hydroxybutyrate as initiation material, carry out esterification with alcohol, obtain intermediate i；
(2) intermediate i is carried out condensation reaction with halogenated acetic acids ester, obtain intermediate ii；
(3) intermediate ii is carried out ring closure reaction and obtain intermediate；
(4) intermediate is carried out ammonolysis reaction, obtain 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 response type and sequencing, thus obtaining the oxiracetam product of more than 20% more satisfactory yield, opens above
Article one, new oxiracetam synthetic route.
Preferably, the halogenated acetic acids ester in above-mentioned steps (2) preferably employs 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 mixes 4- amino -3-hydroxybutyrate and the alcohol of 5～20 times of weight
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；Obtain the alcoholic solution containing intermediate i, then from the alcoholic solution containing intermediate i
Collect intermediate i；Described alcohol is methanol, ethanol, normal propyl alcohol, isopropanol, n-butyl alcohol, the tert-butyl alcohol, Hexalin or cyclopentanol；Described
Acylating agent is concentrated hydrochloric acid, concentrated sulphuric acid, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride or oxalyl chloride；Described catalyst be concentrated sulphuric acid,
Loprazolam, p-methyl benzenesulfonic acid or trifluoroacetic acid.
Specifically, above-mentioned (2) step: be the intermediate i that will obtain 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；Described solvent select methanol, ethanol, isopropanol, oxolane, in dmf, dmso one
Plant or multiple combination；Described base catalyst is preferably pyridine, triethylamine, lutidines, potassium carbonate or sodium bicarbonate；Middle
Body i with the mol ratio of halogenated acetic acids ester is: 1:1～3, and intermediate i with the mol ratio of described base catalyst is: 1:2～3.
The invention has the following beneficial effects:
Oxiracetam synthetic route of the present invention is one and is suitable to the synthetic route of industrialized production, is especially advantageous for dividing of product
From purification, synthetic route of the present invention at least can obtain (s)-oxiracetam or the DL body Aura west of more than 20% more satisfactory yield
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 obtains 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, and purification is without column chromatography, low cost, easy and simple to handle, better quality.The present invention opens
Article one, new oxiracetam synthetic route.
Specific embodiment
Below by embodiment, the present invention is specifically described it is necessary to it is pointed out here that, following examples are only used
In being further detailed it is impossible to be interpreted as limiting the scope of the invention to the present invention, being skilled in technique of this field
Personnel can make some nonessential improvement according to foregoing invention content and adjust 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 i:
Take raw material s-4- amino -3-hydroxybutyrate 50g, add in a single neck bottle, add methanol 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,
Drip solid when making a concentrated effort to finish to dissolve again, eventually form a faint yellow supernatant liquid.Continue stirring 3 hours, raw material base is shown in by point plate
This reaction is complete, stopped reaction, directly concentrates removing solvent and obtains pale yellow oil, curing at low temperatures obtains intermediate i.Through core
Magnetic testi, intermediate i is: 1h-nmr (300mhz, d2o): δ 2.76-2.67 (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 i is:R1 is first
Base.
(2) preparation of intermediate ii
The intermediate i that step (1) is obtained is dissolved in the methanol 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, start Deca bromoacetate 90ml (2eq), Deca process is put
Thermal phenomenon, continues stirring 2 hours after completion of dropping, point plate is shown in raw material reaction completely, and stopped reaction adds ea (ethyl acetate)
500ml, water 300ml, solid is completely dissolved, and water layer solid sodium chloride saturation separates organic layer, 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 aqueous phase, organic faciess discard, and aqueous phase continues
Continuous sodium bicarbonate adjusts ph to 8, solid sodium chloride saturation, and ea 300ml extracts three times, merges organic faciess, and anhydrous magnesium sulfate is done
Dry, concentrate removing solvent and obtain pale yellow oil, 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
The intermediate ii that step (2) is obtained is dissolved with 500ml ethanol, 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.Stopped reaction, concentrates and removes ethanol, adds ea (ethyl acetate) dissolving, crosses and filter
Desalt, activated carbon decolorizing, concentrate remove yellow oil obtains intermediate.Through nuclear-magnetism detection, intermediate 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:
R2 is ethyl.
(4) preparation of (s)-oxiracetam
The intermediate that step (3) is obtained adds strong aqua ammonia 200ml, is stirred at room temperature 18 hours, and raw material reaction is shown in by point plate
Completely, stopped reaction, concentrates and removes eliminating water and ammonia, obtains yellow oil, adds acetone solution grease, adds a small amount of crystal seed
Stirring, separates out 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 this dissolving crude product in the water of 100ml, heating makes it dissolve, and activated carbon decolorizing half is little
When, it is filtered to remove activated carbon, crystallisation by cooling, 5 DEG C stand overnight, next day filters to obtain white solid 32g, purity 99.9%, isomery
Body ratio 0.1%, yield is 48.2%, through nuclear-magnetism detection, levo-oxiracetam: 1h-nmr (300mhz, dmso-d6) δ 2.10
(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 accounting for its 18 times of weight, stirring, react esterification 5 at 60 DEG C
About hour, raw material fundamental reaction is complete, stopped reaction, directly concentrates and removes solvent, and curing at low temperatures obtains intermediate i；With
When above solvent additionally use methanol, normal propyl alcohol, isopropanol, n-butyl alcohol, the tert-butyl alcohol, Hexalin or cyclopentanol etc. to prepare centre
Body i, after through nuclear-magnetism detection, obtained intermediate 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) the intermediate i that will obtain from step (1), in the ethanol of 15 times of weight of s-4- amino -3-hydroxybutyrate,
Stirring cools down, 60 DEG C of condensation reactions of Deca bromoacetic acid N-butyl 10 hours, and described intermediate i with the mol ratio of halogenated acetic acids ester is
1:1.5, then collects and obtains intermediate ii, and above solvent additionally uses methanol, isopropanol, oxolane, dmf or dmso simultaneously
Etc. preparing intermediate ii, after through nuclear-magnetism detection, obtained intermediate ii is: 1h-nmr (300mhz, d2o): δ 0.96
(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) the intermediate ii obtaining step (2), is dissolved in ethyl acetate, described intermediate ii and ethyl acetate
Mol ratio is 1:12, is warming up at 85 DEG C and carries out ring closure reaction 6.5 hours, obtains the solution containing intermediate, then from containing
Have to collect in the solution of intermediate and obtain intermediate, described solvent additionally uses as ethanol, the tert-butyl alcohol, toluene, diformazan
Benzene, water, butyl acetate or ethyl n-butyrate., after through nuclear-magnetism detection, obtained intermediate 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 that step (3) obtains is added in strong aqua ammonia, be stirred at room temperature and carry out ammonolysis reaction 15 hours, institute
State intermediate: the mol ratio of ammonia is intermediate: ammonia=1:13, in terms of the ammonia in ammonia methanol solution；Reaction concentrates completely
Remove eliminating water and ammonia, using acetone purification, crystallization obtains product (s)-oxiracetam crude product.By dissolving crude product in water, heating is molten
Solution, activated carbon decolorizing, it is filtered to remove activated carbon, concentrating under reduced pressure eliminating water, stop when surplus water is and adds 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 measures its purity, calculates and must receive
Rate is 20%, and through nuclear-magnetism detection, gained levo-oxiracetam is: 1h-nmr (300mhz, dmso-d6) δ 2.10 (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: the embodiment optimizing further for the present invention with respect to embodiment 2, by table 1 below step and
Parameter is carried out, other same as Example 1.
Table 1
Through nuclear-magnetism detection, the intermediate of embodiment 3-12 preparation is as shown in table 2 with levo-oxiracetam:
Measure its purity in 99.5-99.9% by the levo-oxiracetam that above example 3-12 is obtained through hplc, 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 accounting for its 18 times of weight, stirring, little in 60 DEG C of reaction esterifications 5
When about, raw material fundamental reaction completely, stopped reaction, directly concentrate removing solvent, curing at low temperatures obtains intermediate i；Simultaneously
Above solvent additionally uses methanol, normal propyl alcohol, isopropanol, n-butyl alcohol, the tert-butyl alcohol, Hexalin or cyclopentanol etc. to prepare intermediate
I, after through nuclear-magnetism detection, obtained intermediate 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) the intermediate i that will obtain from step (1), in the ethanol of 15 times of weight of 4- amino -3-hydroxybutyrate, stirs
Mix cooling, 60 DEG C of condensation reactions of Deca bromoacetic acid N-butyl 10 hours, described intermediate i is 1 with the mol ratio of halogenated acetic acids ester:
1.5, then collect and obtain intermediate ii, above solvent additionally uses methanol, isopropanol, oxolane, dmf or dmso etc. simultaneously
To prepare intermediate ii, after through nuclear-magnetism detection, obtained intermediate ii is: 1h-nmr (300mhz, d2o): δ 0.95 (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) the intermediate ii obtaining step (2), is dissolved in ethyl acetate, described intermediate ii and ethyl acetate
Mol ratio is 1:12, is warming up at 85 DEG C and carries out ring closure reaction 6.5 hours, obtains the solution containing intermediate, then from containing
Have to collect in the solution of intermediate and obtain intermediate, described solvent additionally uses as ethanol, the tert-butyl alcohol, toluene, diformazan
Benzene, water, butyl acetate or ethyl n-butyrate., after through nuclear-magnetism detection, obtained intermediate 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 that step (3) obtains is added in strong aqua ammonia, be stirred at room temperature and carry out ammonolysis reaction 15 hours, institute
State intermediate: the mol ratio of ammonia is intermediate: ammonia=1:13, in terms of the ammonia in ammonia methanol solution；Reaction concentrates completely
Remove eliminating water and ammonia, using acetone purification, crystallization obtains product (s)-oxiracetam crude product.By dissolving crude product in water, heating is molten
Solution, activated carbon decolorizing, it is filtered to remove activated carbon, concentrating under reduced pressure eliminating water, stop when surplus water is and adds 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 measures its purity, calculates
Yield is 19.5%, and through nuclear-magnetism detection, gained DL body oxiracetam is: 1h-nmr (300mhz, dmso-d6) δ 2.05 (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 (9)
1. a kind of synthetic method of (s)-oxiracetam is it is characterised in that reaction expression is as follows:
Wherein r1For methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, isobutyl group, cyclopenta or cyclohexyl；Described r2
For ethyl, n-pro-pyl, 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, carry out esterification with alcohol, obtain intermediate i；
(2) intermediate i is carried out condensation reaction with halogenated acetic acids ester, obtain intermediate ii；
(3) intermediate ii is carried out ring closure reaction and obtain intermediate；
(4) intermediate is carried out ammonolysis reaction, obtain target product (s)-oxiracetam；
Described step (2) is the intermediate i that will obtain from step (1), exists in base catalyst with halogenated acetic acids ester in a solvent
Lower reaction 5～10 hours, reaction temperature is 20～55 DEG C, then collects and obtains intermediate ii；Described solvent may be selected methanol, second
Alcohol, isopropanol, oxolane, one or more of dmf, dmso combination；Described base catalyst be pyridine, triethylamine, two
Picoline, potassium carbonate or sodium bicarbonate；Described intermediate i with the mol ratio of halogenated acetic acids ester is: 1:1～3, intermediate i with
The mol ratio of described base catalyst is: 1:2～3；
Described step (3) is the intermediate ii 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, then collects from the solution containing intermediate and obtains centre
Body；Described solvent may be selected: ethanol, the tert-butyl alcohol, toluene, dimethylbenzene, water, ethyl acetate, butyl acetate or ethyl n-butyrate..
2. as claimed in claim 1 (s)-oxiracetam synthetic method it is characterised in that: the alcohol in described step (1) is first
Alcohol, ethanol, normal propyl alcohol, isopropanol, n-butyl alcohol, the tert-butyl alcohol or cyclopentanol.
3. as claimed in claim 1 (s)-oxiracetam synthetic method it is characterised in that: the halo second in described step (2)
Acid esters is chloracetic acid ester or monobromo-acetic acid ester.
4. as claimed in claim 3 (s)-oxiracetam synthetic method it is characterised in that: the bromo second in described step (2)
Acid esters is bromoacetate, bromoacetic acid N-butyl, bromide isobutyl acetate, bromo-acetic acid tert-butyl or benzyl acetate bromide.
5. as described in any one of claim 1-4 (s)-oxiracetam synthetic method it is characterised in that:
Described (1) step is to add in alcohol by s-4- amino -3-hydroxybutyrate, under conditions of instilling acylating agent or catalyst,
Carry out esterification and obtain intermediate i；Described acylating agent is concentrated hydrochloric acid, concentrated sulphuric acid, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride
Or oxalyl chloride；Described catalyst is concentrated sulphuric acid, Loprazolam, p-methyl benzenesulfonic acid or trifluoroacetic acid；Described acylating agent or catalyst
Mol ratio with s-4- amino -3-hydroxybutyrate is: s-4- amino -3-hydroxybutyrate: acylating agent or catalyst=1:1～2.5；
Described step (2) is the intermediate i that will obtain from step (1), exists in base catalyst with halogenated acetic acids ester in a solvent
Lower reaction 5～10 hours, reaction temperature is 20～55 DEG C, then collects and obtains intermediate ii；Described solvent may be selected methanol, second
Alcohol, isopropanol, oxolane, one or more of dmf, dmso combination；Described base catalyst be pyridine, triethylamine, two
Picoline, potassium carbonate or sodium bicarbonate；Described intermediate i with the mol ratio of halogenated acetic acids ester is: 1:1～3, intermediate i with
The mol ratio of described base catalyst is: 1:2～3；
Described step (3) is the intermediate ii 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, then collects from the solution containing intermediate and obtains centre
Body；Described solvent may be selected: ethanol, the tert-butyl alcohol, toluene, dimethylbenzene, water, ethyl acetate, butyl acetate or ethyl n-butyrate.；
Described step (4) is the intermediate obtaining step (3), reacts 4～16 hours at 20～30 DEG C with strong aqua ammonia, so
Target product (s)-oxiracetam is collected afterwards from product；Described intermediate: the mol ratio of ammonia is intermediate: ammonia=
1:12～15, in terms of the ammonia in ammonia methanol solution.
6. a kind of synthetic method of oxiracetam is it is characterised in that comprise the steps:
(1) with 4- amino -3-hydroxybutyrate as initiation material, carry out esterification with alcohol, obtain intermediate i；
(2) intermediate i is carried out condensation reaction with halogenated acetic acids ester, obtain intermediate ii；
(3) intermediate ii is carried out ring closure reaction and obtain intermediate；
(4) intermediate is carried out ammonolysis reaction, obtain target product oxiracetam；
Alcohol in described step (1) is methanol, ethanol, normal propyl alcohol, isopropanol, n-butyl alcohol, the tert-butyl alcohol, Hexalin or cyclopentanol；
Described (2) step is the intermediate i that will obtain 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 20～55 DEG C, then collect and obtain
Obtain intermediate ii；Described solvent selects methanol, ethanol, isopropanol, oxolane, one or more of dmf, dmso combination；
Described base catalyst is pyridine, triethylamine, lutidines, potassium carbonate or sodium bicarbonate；Intermediate i and halogenated acetic acids ester
Mol ratio is: 1:1～3, and intermediate i with the mol ratio of described base catalyst is: 1:2～3；Described 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；
Described step (3) is the intermediate ii 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, then collects from the solution containing intermediate and obtains centre
Body；Described solvent may be selected: ethanol, the tert-butyl alcohol, toluene, dimethylbenzene, water, ethyl acetate, butyl acetate or ethyl n-butyrate..
7. the synthetic method of oxiracetam as claimed in claim 6 is it is characterised in that described (1) step is:
4- amino -3-hydroxybutyrate is added in alcohol, under conditions of instilling acylating agent or catalyst, carries out esterification and obtain
Intermediate i；Described alcohol is methanol, ethanol, normal propyl alcohol, isopropanol, n-butyl alcohol, the tert-butyl alcohol, Hexalin or cyclopentanol；Described acylation
Agent is concentrated hydrochloric acid, concentrated sulphuric acid, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride or oxalyl chloride；Described catalyst is concentrated sulphuric acid, methane
Sulfonic acid, p-methyl benzenesulfonic acid or trifluoroacetic acid.
8. oxiracetam as claimed in claim 7 synthetic method it is characterised in that: described acylating agent or catalyst and 4- ammonia
The mol ratio of base -3-hydroxybutyrate is: 4- amino -3-hydroxybutyrate: acylating agent or catalyst=1:1～2.5.
9. oxiracetam as claimed in claim 1 synthetic method it is characterised in that:
Described (1) step is to add 4- amino -3-hydroxybutyrate in alcohol, under conditions of instilling acylating agent or catalyst, enters
Row esterification obtains intermediate i；Described acylating agent be concentrated hydrochloric acid, concentrated sulphuric acid, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride or
Oxalyl chloride；Described catalyst is concentrated sulphuric acid, Loprazolam, p-methyl benzenesulfonic acid or trifluoroacetic acid；Described acylating agent or catalyst with
The mol ratio of 4- amino -3-hydroxybutyrate is: 4- amino -3-hydroxybutyrate: acylating agent or catalyst=1:1～2.5；
Described step (2) is the intermediate i that will obtain from step (1), exists in base catalyst with halogenated acetic acids ester in a solvent
Lower reaction 5～10 hours, reaction temperature is 20～55 DEG C, then collects and obtains intermediate ii；Described solvent may be selected methanol, second
Alcohol, isopropanol, oxolane, one or more of dmf, dmso combination；Described base catalyst be pyridine, triethylamine, two
Picoline, potassium carbonate or sodium bicarbonate；Described intermediate i with the mol ratio of halogenated acetic acids ester is: 1:1～3, intermediate i with
The mol ratio of described base catalyst is: 1:2～3；
Described step (3) is the intermediate ii 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, then collects from the solution containing intermediate and obtains centre
Body；Described solvent may be selected: ethanol, the tert-butyl alcohol, toluene, dimethylbenzene, water, ethyl acetate, butyl acetate or ethyl n-butyrate.；
Described step (4) is the intermediate obtaining step (3), reacts 4～16 hours at 20～30 DEG C with strong aqua ammonia, so
Target product oxiracetam is collected afterwards from product；Described intermediate: the mol ratio of ammonia is intermediate: ammonia=1:12
～15, in terms of the ammonia in ammonia methanol solution.
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| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| BR112021017623A2 (en) | 2019-03-06 | 2021-11-09 | Xianfeng Peng | Use of ?-quaternary ammonium butyrate compound in the preparation of additives for animal feed |
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