CN105968024A - Synthesis method of oxiracetam - Google Patents

Synthesis method of oxiracetam Download PDF

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Publication number
CN105968024A
CN105968024A CN201610560643.0A CN201610560643A CN105968024A CN 105968024 A CN105968024 A CN 105968024A CN 201610560643 A CN201610560643 A CN 201610560643A CN 105968024 A CN105968024 A CN 105968024A
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alcohol
intermediate compound
butyl
compound
oxiracetam
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袁华杰
代丽萍
谢玲玲
叶雷
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Sichuan hundred road environmental protection Mstar Technology Ltd
Sichuan hundred road Medicine Co., Ltd.
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CHENGDU BIOTOP PHARMA TECHNOLOGY CO LTD
Chongqing Runze Pharmaceutical Co Ltd
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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
    • 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
    • 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

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The invention relates to a synthesis method of (S)-oxiracetam. The method comprises the following steps: (1) carrying out an esterification reaction on alcohol and S-4-amino-3-hydroxybutyrate taken as a starting material to obtain an intermediate I; (2) enabling the intermediate I and halogenated acetic ester to be subjected to a condensation reaction to obtain an intermediate II; (3) carrying out a ring closing reaction on the intermediate II to obtain an intermediate III; and (4) carrying out an ammonolysis reaction on the intermediate III to obtain the target product (S)-oxiracetam. After the synthesis route of the oxiracetam is adopted, the (S)-oxiracetam with more ideal yield of 20% or more is at least obtained; and therefore, a new oxiracetam synthesis route is opened up.

Description

A kind of synthetic method of oxiracetam
The application is Application No. " 201310243165.7 ", invention entitled " a kind of Aura Western smooth synthetic method " the divisional application of application for a patent for invention.
Technical field
The present invention relates to the synthetic method of a kind of oxiracetam, particularly relate to one (S)-Aura west Smooth synthetic method.
Background technology
Oxiracetam is the nootropics synthesized first in 1974 than Qie Mu company by Italy SmithKline Medicine, is by two kinds of isomer (S)-oxiracetams ((S)-oxiracetam) and (R)-oxiracetam The raceme that ((R)-oxiracetam) forms.(S)-oxiracetam be one of oxiracetam single Enantiomer, chemistry is entitled: (S)-4-hydroxyl-2 oxo-1-pyrrolidine ethanamide.Nootropics Aura Western smooth be hydroxy-amino-butyric acid (GABOB) derivant of a kind of synthesis, it is a kind of to promote Study, memory reinforcing, the medicine for central nervous system of protection 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 the synthetic method of a kind of (S)-oxiracetam: (S)-4-amino-3-hydroxybutyrate is initiation material, protects hydroxyl, ring through sillylation reagent Product after conjunction reacts 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 has A lot of shortcomings, can increase reactions steps as used protection group that hydroxyl is carried out protection, waste raw material, Time-consuming longer, increase cost, make total recovery reduce.It addition, in this course of reaction, need Intermediate is carried out column chromatography purification, just can carry out next step reaction.These shortcomings are for work It is all the most disadvantageous for industry large-scale production.
Document: Tetrahedron:Asymmetry 1992,3 (11) reports a kind of this change of synthesis The method of compound；With malic acid and glycine methyl ester as initiation material, chloroacetic chloride protection hydroxyl, Chosen property is reduced, and goes hydroxyl, Deprotection, ammonolysis, obtains target compound.At this In method, need to carry out a selective reduction and cause the multiple by-product of generation, and each Intermediate is required for column chromatography purification, just can carry out next step reaction.Such technique is the most not The requirement of industrially scalable can be met.
Technology disclosed in patent W02005/115978, wherein (S)-4-chloro-3-hydroxyl ethyl n-butyrate. React with Aminoacetamide and obtain target compound, or react with glycine ethyl ester, then through ammonolysis Obtain target compound.Wherein (S)-4-chloro-3-hydroxybutanoic acid ester and sweet amine amide are in alkalescence condition It is the alkali controlling reactant liquor by disposably adding alkali that lower reaction obtains final products oxiracetam Property, but owing to oxiracetam is more easily damaged in strong base solution, so directly affects Aura Western smooth purity and yield；In purification final products oxiracetam, additionally use silica gel column chromatography Method, the eluent of use is organic mixed solvent, and quantity of solvent is big, is not easily recycled, and cost is high, And silica gel column chromatography method is also not suitable for industrial amplification production.
Chinese patent CN10575309A reports a kind of with glycine and S-4-halogen-3-hydroxyl fourth Acid esters is that raw material is condensed, then carries out being esterified the synthetic route of ammonolysis, but the method is same The mode dripping highly basic under hot conditions is used to be condensed, can be with S-4-while condensation The multiple side reactions such as halogen-3-hydroxybutyrate ester hydrolysis, cause being condensed yield relatively low, and by-product is relatively Many, obtain end-product S-oxiracetam and cannot separate out by direct crystallization under this purity, need ion The chromatography remove impurity of exchanger resin, cost is high, and purity is low, it is difficult to industrialization.
Summary of the invention
It is an object of the invention to provide the synthetic method of a kind of oxiracetam, the inventive method is grasped Make simple, purity height, yield height.
The object of the invention is achieved through the following technical solutions:
The synthetic method of a kind of (S)-oxiracetam, comprises the steps:
(1) with S-4-amino-3-hydroxybutyrate as initiation material, esterification is carried out with alcohol, To intermediate compound I；
(2) intermediate compound I and halogenated acetic acids ester are carried out condensation reaction, it is thus achieved that intermediate II；
(3) intermediate II is carried out ring closure reaction and obtain intermediate III；
(4) intermediate III 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 route and has all been difficult to obtain (S)-oxiracetam, final by above synthetic route, the most suitable by above each response type and priority Sequence coordinate thus obtain (S)-oxiracetam product of more than 20% more satisfactory yield, open Article one, new oxiracetam synthetic route.
So that impurity is more easily separated, operating procedure is simple, thus obtain high-purity product, Promote the industrialization of pharmaceutical production, the most also ensure reaction yield, in above-mentioned steps (2) Halogenated acetic acids ester preferably employs bromoacetate, ethyl chloroacetate, bromoacetic acid N-butyl, bromine second Acid isobutyl ester, bromo-acetic acid tert-butyl or benzyl acetate bromide.
Reaction yield is improved further, above-mentioned (1) in order to improve reactivity further It is preferably a step:
S-4-amino-3-hydroxybutyrate is added in alcohol, also instilling acylating agent or the bar of catalyst Under part, carry out esterification and obtain intermediate compound I；The optional methanol of described alcohol, ethanol, normal propyl alcohol, Isopropanol, n-butyl alcohol, the tert-butyl alcohol, Hexalin or cyclopentanol, 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 be concentrated sulphuric acid, Loprazolam, to toluene sulphur Acid or trifluoroacetic acid.
Intermediate compound 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, improve reaction yield, above-mentioned acylating agent or catalysis Agent with the mol ratio of S-4-amino-3-hydroxybutyrate is: S-4-amino-3-hydroxybutyrate: acylating agent Or catalyst=1:1～2.5.
More specifically, above-mentioned (1) step is:
First the above-mentioned alcohol of S-4-amino-3-hydroxybutyrate and 5～20 times of weight is mixed, be subsequently adding Above-mentioned acylating agent or catalyst react 1～5 hour at 0～60 DEG C, S-4-amino-3-hydroxyl fourth Acid is 1:1.5～1.65 with acylating agent or catalyst molar ratio；Obtain the alcohol containing intermediate compound I Solution, then collects intermediate compound I from the alcoholic solution containing intermediate compound I.
Above-mentioned S-4-amino-3-hydroxybutyrate, alcohol and acylating reagent are commercially available prod.
Above-mentioned (2) step, specifically, is the intermediate compound I that will obtain from step (1), at 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 and obtain intermediate II；Described solvent without particular/special requirement, prioritizing selection methanol, One or more combinations in ethanol, isopropanol, oxolane, DMF, DMSO；Institute The base catalyst said is preferably pyridine, triethylamine, lutidines, potassium carbonate or sodium bicarbonate.
In order to further improve reaction purity and yield, intermediate compound I is rubbed with halogenated acetic acids ester That ratio is: 1:1～3, intermediate compound I with the mol ratio of described base catalyst is: 1:2～3.
Most specifically say that above-mentioned (2) step is the intermediate compound I that will obtain from step (1), With halogenated acetic acids ester in base catalysis in the solvent of the 10-15 times of weight of S-4-amino-3-hydroxybutyrate Reacting 5～10 hours in the presence of agent, reaction temperature is 0～60 DEG C, then collects in the middle of obtaining Body II；Described solvent is without particular/special requirement, prioritizing selection methanol, ethanol, isopropanol, tetrahydrochysene furan Mutter, one or more combinations in DMF, DMSO；Described base catalyst is preferably pyrrole Pyridine, triethylamine, lutidines, potassium carbonate or sodium bicarbonate；Intermediate compound I and halogenated acetic acids The mol ratio of ester is: 1:1～3, and intermediate compound I with the mol ratio of described base catalyst 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, tertiary fourth Base, isobutyl group, benzyl or cyclopenta etc..
Above-mentioned steps (3), specifically, the intermediate II that step (2) is obtained, in a solvent Carrying out ring closure reaction under the conditions of 50～130 DEG C, the time is 3～8 hours, it is thus achieved that containing intermediate The solution of III, then collects from the solution containing intermediate III and obtains intermediate III；Described Solvent may select: 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 III 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 with the mol ratio of solvent is 1:10～30.
Above-mentioned steps (4), specifically, the intermediate III step (3) obtained, at 20～30 DEG C React 4～16 hours with strong aqua ammonia down, from product, then collect target product (S)-Austria La Xitan.
Overall yield of reaction is improved, above-mentioned intermediate III in order to improve reactivity further: The mol ratio of ammonia is intermediate III: ammonia=1:12～15, in terms of the ammonia in ammonia methanol solution； Described strong aqua ammonia is known in the art, and the concentrations by weight of its solution is 25～about 28%.
The method collecting target product (S)-oxiracetam from the product of above-mentioned steps (4), The most as follows: product is dissolved in the water, heating for dissolving, activated carbon decolorizing, Being filtered to remove activated carbon, concentrating under reduced pressure removes water, when surplus water is for adding products weight 2～3 Times time stop concentrating, the crystallization of 0～5 DEG C of sub-cooled, it is thus achieved that product (S)-oxiracetam.
The synthetic method of a kind 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, in obtaining Mesosome I；
(2) intermediate compound I and halogenated acetic acids ester are carried out condensation reaction, it is thus achieved that intermediate II；
(3) intermediate II is carried out ring closure reaction and obtain intermediate III；
(4) intermediate III is carried out ammonolysis reaction, obtain target product oxiracetam.
Inventor has attempted a lot of new synthesis route and has all been difficult to obtain oxiracetam, final by above conjunction Become route, by above each response type and the cooperation of sequencing thus obtain more than 20% relatively The oxiracetam product of ideal recovery, opens a new oxiracetam synthetic route.
Preferably, the halogenated acetic acids ester in above-mentioned steps (2) preferably employ bromoacetate, Ethyl chloroacetate, bromoacetic acid N-butyl, bromide isobutyl acetate, bromo-acetic acid tert-butyl or bromoacetic acid Benzyl ester.
Further preferably saying, above-mentioned (1) step is: first by 4-amino-3-hydroxybutyrate with The alcohol mixing of 5～20 times of weight, is subsequently adding acylating agent or catalyst and reacts at 0～60 DEG C 1～5 hour, 4-amino-3-hydroxybutyrate and acylating agent or catalyst molar ratio be 1:1.5～ 1.65；Obtain the alcoholic solution containing intermediate compound I, then from the alcoholic solution containing intermediate compound I Collect intermediate compound I；Described alcohol is methanol, ethanol, normal propyl alcohol, isopropanol, n-butyl alcohol, uncle Butanol, Hexalin or cyclopentanol；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, right Toluenesulfonic acid or trifluoroacetic acid.
Specifically, above-mentioned (2) step: be the intermediate compound I that will obtain from step (1), at 4- With halogenated acetic acids ester at base catalyst in the solvent of the 10-15 times of weight of amino-3-hydroxybutyrate In the presence of react 5～10 hours, reaction temperature is 0～60 DEG C, then collect obtain intermediate II；Described solvent selects in methanol, ethanol, isopropanol, oxolane, DMF, DMSO One or more combination；Described base catalyst is preferably pyridine, triethylamine, dimethyl pyrazole Pyridine, potassium carbonate or sodium bicarbonate；Intermediate compound I with the mol ratio of halogenated acetic acids ester is: 1:1～3, Intermediate compound I with the mol ratio of described base catalyst is: 1:2～3.
There is advantages that
Oxiracetam synthetic route of the present invention is one and is suitable to the synthetic route of industrialized production, non- Often being beneficial to the isolated and purified of product, it is more satisfactory that synthetic route of the present invention at least can obtain more than 20% (the S)-oxiracetam of yield or DL body oxiracetam product, open a new Aura west Smooth synthetic route.Meanwhile, synthetic route of the present invention is obtained by further optimal control condition Finally (S)-oxiracetam or the purity of DL body oxiracetam product and optical purity all up to More than 99.9%, total recovery reaches 48.2%.Meanwhile, the present invention (S)-oxiracetam or mixed is used Rotation body oxiracetam synthetic method compared with prior art, raw material is cheap and easy to get, purification without Need column chromatography, low cost, easy and simple to handle, better quality.The present invention opens a new Austria La Xitan synthetic route.
Detailed description of the invention
Below by embodiment, the present invention is specifically described, it is necessary to it is pointed out here that, Following example are served only for being further detailed the present invention, it is impossible to be interpreted as the present invention The restriction of protection domain, the person skilled in the art in this field can be according to foregoing invention content to this Some nonessential improvement and adjustment are made in invention.
Embodiment 1
A kind of synthetic method of (S)-oxiracetam, it carries out as follows,
The preparation of (l) intermediate compound I:
Take raw material S-4-amino-3-hydroxybutyrate 50g, add in a single neck bottle, add methanol 50ml, Stirring, ice-water bath cools down, and is slowly dropped into concentrated hydrochloric acid 150ml, keeps temperature to be less than 40 DEG C, Solid first has a course of dissolution, separates out the most again, drips solid when making a concentrated effort to finish and dissolves again, One faint yellow supernatant liquid of rear formation.Continuing stirring 3 hours, raw material fundamental reaction is shown in by some plate Completely, stopped reaction, directly concentrate removing solvent and obtain pale yellow oil, curing at low temperatures obtains To intermediate compound I.Detecting through nuclear-magnetism, 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) obtains is dissolved in the methanol of 500ml, is cooled to outer temperature 0 DEG C, add potassium carbonate 173g (3eq), have a large amount of solid to generate, stir five minutes, start Dropping bromoacetate 90ml (2eq), dropping process has exothermic phenomenon, drips complete follow-up Continuous stirring 2 hours, puts plate and sees that raw material reaction is complete, and stopped reaction adds EA (acetic acid second Ester) 500ml, water 300ml, solid is completely dissolved, by saturated for water layer solid sodium chloride, Separating organic layer, water layer EA200ml is extracted twice, and merges organic layer, organic layer 2M Hydrochloric acid 200ml wash three times, merge hydrochloric acid aqueous phase, organic facies discards, and aqueous phase continues to use carbonic acid Hydrogen sodium regulation pH to 8, solid sodium chloride is saturated, and EA 300ml extracts three times, merges organic Phase, anhydrous magnesium sulfate is dried, and concentrates removing solvent and obtains pale yellow oil, curing at low temperatures Obtain intermediate II.Detect through nuclear-magnetism, intermediate II: 1H-NMR (300MHz, D2O): δ 1.3 (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
Intermediate II 500ml ethanol step (2) obtained dissolves, and is warming up to 75 DEG C, Refluxing 8 hours, obtain a red tan solution, some plate is shown in that raw material reaction is complete.Stopped reaction, Concentrating and remove ethanol, add EA (ethyl acetate) and dissolve, be filtered to remove salt, activated carbon takes off Color, concentrate remove yellow oil obtains intermediate III.Detecting 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) obtains is added strong aqua ammonia 200ml, is stirred at room temperature 18 hours, Point plate is shown in that raw material reaction is complete, and stopped reaction concentrates and removes water and ammonia, obtains yellow oily Thing, adds acetone solution grease, adds the stirring of a small amount of crystal seed, 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, Activated carbon decolorizing half an hour, being filtered to remove activated carbon, crystallisation by cooling, 5 DEG C stand overnight, next day Filtering to obtain white solid 32g, purity 99.9%, isomer proportion 0.1%, yield is 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
1, the synthetic method of a kind of (S)-oxiracetam, as follows:
(1) by S-4-amino-3-hydroxybutyrate and the ethanol accounting for its 18 times of weight, stirring, 60 DEG C of reaction esterifications about 5 hours, raw material fundamental reaction is complete, stopped reaction, directly Concentrating and remove solvent, curing at low temperatures obtains intermediate compound I；Above solvent additionally uses first simultaneously In prepared by alcohol, normal propyl alcohol, isopropanol, n-butyl alcohol, the tert-butyl alcohol, Hexalin or cyclopentanol etc. Mesosome I, after detect through nuclear-magnetism, 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 obtain from step (1), at S-4-amino-3-hydroxybutyrate In the ethanol of 15 times of weight, stirring cooling, drip 60 DEG C of condensation reactions 10 of bromoacetic acid N-butyl Hour, described intermediate compound I is 1:1.5 with the mol ratio of halogenated acetic acids ester, then collects in obtaining Mesosome II, simultaneously above solvent additionally use methanol, isopropanol, oxolane, DMF or DMSO etc. prepare intermediate II, 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 step (2) obtained, is dissolved in ethyl acetate, described centre Body II is 1:12 with the mol ratio of ethyl acetate, is warming up at 85 DEG C carry out ring closure reaction 6.5 Hour, it is thus achieved that containing the solution of intermediate III, then collect from the solution containing intermediate III Obtain intermediate III, described solvent additionally use into ethanol, the tert-butyl alcohol, toluene, dimethylbenzene, Water, butyl acetate or ethyl n-butyrate., after detect through nuclear-magnetism, 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 that step (3) obtains is added in strong aqua ammonia, be stirred at room temperature and carry out ammonolysis React 15 hours, described intermediate III: the mol ratio of ammonia is intermediate III: ammonia=1:13, In terms of the ammonia in ammonia methanol solution；Reaction concentrates remove water and ammonia completely, uses acetone purification, Crystallization obtains product (S)-oxiracetam crude product.By dissolving crude product in water, heating for dissolving, live Property carbon decoloring, be filtered to remove activated carbon, concentrating under reduced pressure remove water, when surplus water for add product Weight 2～stop when 3 times concentrating, 0～5 DEG C of sub-cooled crystallization, it is thus achieved that product (S)-Aura west Smooth.It is 80.4% that HPLC measures its purity, calculate yield is 20%, through nuclear-magnetism detect, institute Obtaining 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: the embodiment optimized further for the present invention relative to embodiment 2, Step and parameter by table 1 below are carried out, other same as in Example 1.
Table 1
Detecting through nuclear-magnetism, intermediate prepared by embodiment 3-12 is as shown in table 2 with levo-oxiracetam:
The levo-oxiracetam prepared by above example 3-12 measures its purity through HPLC and exists 99.5-99.9%, calculate yield at 35-45%.
Embodiment 13
1, the synthetic method of a kind of DL body oxiracetam, as follows:
(1) by 4-amino-3-hydroxybutyrate and the ethanol accounting for its 18 times of weight, stirring, at 60 DEG C Reaction esterification about 5 hours, raw material fundamental reaction is complete, and stopped reaction directly concentrates Removing solvent, curing at low temperatures obtains intermediate compound I；Simultaneously above solvent additionally use methanol, Intermediate prepared by normal propyl alcohol, isopropanol, n-butyl alcohol, the tert-butyl alcohol, Hexalin or cyclopentanol etc. I, after detect through nuclear-magnetism, 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 obtain from step (1), at the 15 of 4-amino-3-hydroxybutyrate In the ethanol of times of weight, stirring cooling, dropping 60 DEG C of condensation reactions 10 of bromoacetic acid N-butyl are little Time, described intermediate compound I is 1:1.5 with the mol ratio of halogenated acetic acids ester, then collects in the middle of obtaining Body II, above solvent additionally uses methanol, isopropanol, oxolane, DMF or DMSO simultaneously Etc. preparing intermediate II, after detect through nuclear-magnetism, 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 step (2) obtained, is dissolved in ethyl acetate, described centre Body II is 1:12 with the mol ratio of ethyl acetate, is warming up at 85 DEG C carry out ring closure reaction 6.5 Hour, it is thus achieved that containing the solution of intermediate III, then collect from the solution containing intermediate III Obtain intermediate III, described solvent additionally use into ethanol, the tert-butyl alcohol, toluene, dimethylbenzene, Water, butyl acetate or ethyl n-butyrate., after detect through nuclear-magnetism, 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 that step (3) obtains is added in strong aqua ammonia, be stirred at room temperature and carry out ammonolysis React 15 hours, described intermediate III: the mol ratio of ammonia is intermediate III: ammonia=1:13, In terms of the ammonia in ammonia methanol solution；Reaction concentrates remove water and ammonia completely, uses acetone purification, Crystallization obtains product (S)-oxiracetam crude product.By dissolving crude product in water, heating for dissolving, live Property carbon decoloring, be filtered to remove activated carbon, concentrating under reduced pressure remove water, when surplus water for add product Weight 2～stop when 3 times concentrating, 0～5 DEG C of sub-cooled crystallization, it is thus achieved that product DL body is difficult to understand La Xitan.It is 82.1% that HPLC measures its purity, calculate yield is 19.5%, through nuclear-magnetism examine Surveying, 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 (16)

1. a Formula II compound,
R1 is methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, isobutyl group, Cyclopenta or cyclohexyl；R2 is ethyl, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, Isobutyl group, benzyl or cyclopenta.
2. the preparation method of one kind such as claim 1 Formula II compound, it is characterised in that: by following Compound is transformed；
3. as claimed in claim 2 method, it is characterised in that use following route:
With S-4-amino-3-hydroxybutyrate as initiation material, carry out esterification with alcohol and obtain Intermediate compound I；Intermediate compound I and halogenated acetic acids ester carry out condensation reaction, obtain intermediate II.
4. method as claimed in claim 3, it is characterised in that employing following steps:
S-4-amino-3-hydroxybutyrate is added in alcohol, also adding acylating agent or the bar of catalyst Under part, carry out esterification and obtain intermediate compound I；The optional methanol of described alcohol, ethanol, normal propyl alcohol, Isopropanol, n-butyl alcohol, the tert-butyl alcohol, Hexalin or cyclopentanol, 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 be concentrated sulphuric acid, Loprazolam, to toluene sulphur Acid or trifluoroacetic acid.
5. method as claimed in claim 4, it is characterised in that employing following steps:
First the alcohol of S-4-amino-3-hydroxybutyrate and 5～20 times of weight is mixed, be subsequently adding acyl Agent or catalyst react 1～5 hour at 0～60 DEG C, S-4-amino-3-hydroxybutyrate and acyl Agent or catalyst molar ratio are 1:1.5～1.65；Obtain the alcoholic solution containing intermediate compound I, Then from the alcoholic solution containing intermediate compound I, collect intermediate compound I.
6. the method as described in any one of claim 3-5, it is characterised in that employing following steps:
The intermediate compound I that will obtain, in a solvent with halogenated acetic acids ester in the presence of base catalyst anti- Answering 5～10 hours, reaction temperature is 0～60 DEG C, then collects and obtains intermediate II；Described Solvent selects the one in methanol, ethanol, isopropanol, oxolane, DMF, DMSO Or multiple combination；Described base catalyst is pyridine, triethylamine, lutidines, potassium carbonate Or sodium bicarbonate.
7. method as claimed in claim 6, it is characterised in that employing following steps:
The intermediate compound I that will obtain, 10-15 times of weight molten of S-4-amino-3-hydroxybutyrate Reacting in the presence of base catalyst 5～10 hours with halogenated acetic acids ester in agent, reaction temperature is 0～60 DEG C, then collect and obtain intermediate II；Described solvent selects methanol, ethanol, isopropyl One or more combinations in alcohol, oxolane, DMF, DMSO；Described base catalysis Agent is pyridine, triethylamine, lutidines, potassium carbonate or sodium bicarbonate；Intermediate compound I and halogen Mol ratio for acetas is: 1:1～3, and intermediate compound I with the mol ratio of described base catalyst is: 1:2～3.
8. a preparation method for levo-oxiracetam, by intermediate II compound according to following route It is transformed:
Intermediate II prepares intermediate III by ring closure reaction, and then ammonolysis obtains levo-oxiracetam； Wherein R2 is ethyl, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, isobutyl group, benzyl Or cyclopenta.
9. method as claimed in claim 8, it is characterised in that employing following steps:
Carrying out ring closure reaction under the conditions of intermediate II in a solvent 50～130 DEG C, the time is 3～8 hours, it is thus achieved that containing the solution of intermediate III, then from the solution containing intermediate III Middle collection obtains intermediate III；Described solvent may select: ethanol, the tert-butyl alcohol, toluene, two Toluene, water, ethyl acetate, butyl acetate or ethyl n-butyrate., it is preferred to use ethanol, toluene or Dimethylbenzene.
10. method as claimed in claim 8 or 9, it is characterised in that employing following steps:
By intermediate III, at 20～30 DEG C, react 4～16 hours with strong aqua ammonia, then from Product is collected (S)-oxiracetam.
11. 1 kinds of Formula II compounds,
R1 is methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, isobutyl group, Cyclopenta or cyclohexyl；R2 is ethyl, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, Isobutyl group, benzyl or cyclopenta.
The preparation method of 12. 1 kinds of Formula II compounds as claimed in claim 11, it is characterised in that Employing following steps:
With 4-amino-3-hydroxybutyrate as initiation material, carry out esterification with alcohol and obtain intermediate compound I； Intermediate compound I and halogenated acetic acids ester carry out condensation reaction, obtain intermediate II.
The preparation method of 13. compounds as claimed in claim 12, it is characterised in that use as follows Step:
4-amino-3-hydroxybutyrate is added in alcohol, also adding acylating agent or the condition of catalyst Under, carry out esterification and obtain intermediate compound I；The optional methanol of described alcohol, ethanol, normal propyl alcohol, Isopropanol, n-butyl alcohol, the tert-butyl alcohol, Hexalin or cyclopentanol, 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 be concentrated sulphuric acid, Loprazolam, to toluene sulphur Acid or trifluoroacetic acid；
It is little that intermediate compound I reacts 5～10 with halogenated acetic acids ester in a solvent in the presence of base catalyst Time, reaction temperature is 0～60 DEG C, then collects and obtains intermediate II；Described solvent selects first One or more combinations in alcohol, ethanol, isopropanol, oxolane, DMF, DMSO； Described base catalyst is pyridine, triethylamine, lutidines, potassium carbonate or sodium bicarbonate.
14. methods as described in claim 12 or 13, it is characterised in that employing following steps: First the above-mentioned alcohol of 4-amino-3-hydroxybutyrate and 5～20 times of weight is mixed, be subsequently adding State acylating agent or catalyst to react 1～5 hour at 0～60 DEG C, S-4-amino-3-hydroxybutyrate It is 1:1.5～1.65 with acylating agent or catalyst molar ratio；Obtain the alcohol containing intermediate compound I molten Liquid, then collects intermediate compound I from the alcoholic solution containing intermediate compound I；
The intermediate compound I that will obtain, in the solvent of 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, reaction temperature be 0～ 60 DEG C, then collect and obtain intermediate II；Described solvent without particular/special requirement, prioritizing selection methanol, One or more combinations in ethanol, isopropanol, oxolane, DMF, DMSO；Institute The base catalyst said is preferably pyridine, triethylamine, lutidines, potassium carbonate or sodium bicarbonate； Intermediate compound I with the mol ratio of halogenated acetic acids ester is: 1:1～3, intermediate compound I and described base catalysis The mol ratio of agent is: 1:2～3.
The preparation method of 15. 1 kinds of oxiracetams, is transformed according to following route by Formula II compound: Intermediate II prepares intermediate III by ring closure reaction, and then ammonolysis obtains levo-oxiracetam.
16. methods as claimed in claim 15, it is characterised in that employing following steps:
Formula II compound carries out ring closure reaction under the conditions of 50～130 DEG C in a solvent, and the time is 3～8 hours, it is thus achieved that containing the solution of intermediate III, then from the solution containing intermediate III Middle collection obtains intermediate III；Described solvent may select: ethanol, the tert-butyl alcohol, toluene, two Toluene, water, ethyl acetate, butyl acetate or ethyl n-butyrate., it is preferred to use ethanol, toluene or Dimethylbenzene；
By intermediate III, at 20～30 DEG C, react 4～16 hours with strong aqua ammonia, then from Product is collected target product (S)-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
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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
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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
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
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