CN101177416B - (2'S,3'R,4S)-3-[2'-(N-substituted aminomethyl)-3'-hydroxy butyryl]-4-substituted oxazolidin-2-ketone derivative and preparation method thereof - Google Patents

(2'S,3'R,4S)-3-[2'-(N-substituted aminomethyl)-3'-hydroxy butyryl]-4-substituted oxazolidin-2-ketone derivative and preparation method thereof Download PDF

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CN101177416B
CN101177416B CN2006101180083A CN200610118008A CN101177416B CN 101177416 B CN101177416 B CN 101177416B CN 2006101180083 A CN2006101180083 A CN 2006101180083A CN 200610118008 A CN200610118008 A CN 200610118008A CN 101177416 B CN101177416 B CN 101177416B
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benzyl
ticl
ketone
oxazolidine
aminomethyl
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CN101177416A (en
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张福利
张立明
邱友春
胡猛
谢美华
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Shanghai Institute of Pharmaceutical Industry
Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Abstract

The invention discloses a (2'S, 3'R, 4S)-3-[2'-(N-substituted aminomethyl)-3'- substituted hydroxy and butyryl]-4-substituted oxazolidin -2- one derivatives (I) and the preparation method. The compound is obtained by the condensation of the compound indicated by formula (II) and acetaldehyde in organic solvent under the action of metal catalyst and alkali. And the compound (I) can be used in the synthesis of 4-AA (III), the key raw material of carbapenems antibiotic. The method has the advantages of dramatic stereoselectivity, convenient operation, cheap and easily available reagent and applicability to industrialized production.

Description

(2 ' S, 3 ' R, 4S)-3-[2 '-(N-replaces aminomethyl)-3 '-maloyl group]-4-substituted oxazole alkane-2-ketone derivatives and preparation method thereof
Technical field
The present invention relates to (2 ' S, 3 ' R, 4S)-3-[2 '-(N-replaces aminomethyl)-3 '-maloyl group]-4-substituted oxazole alkane-2-ketone derivatives and preparation method thereof.
Background technology
Carbapenem antibiotic is the β-Nei Xiananleikangshengsu with novel texture that grows up nineteen seventies.This class microbiotic all has very strong inhibition activity to gram-positive microorganism and negative bacterium, aerophil and anerobe, and is highly stable to β-Nei Xiananmei.As the product of a class than the tool future, carbapenem antibiotic is in the fast rise stage at present.
(1 ' R, 3R, 4R)-and 3-(1 '-hydroxyethyl)-4-acetoxyl group azetidine-2-ketone (III) (hereinafter to be referred as 4-AA), be the critical materials of carbapenem antibiotics such as preparation meropenem, ertapenem, biapenem, S-4661.
4-AA synthetic difficult point mainly is how efficiently to introduce three chiral centres easily.JP2134349; JP4173795; JP4173776; JP5239019; EP167154; EP0774463; WO9807691; Chem Pharm Bull, 1992,40:1094-1097; J Chem Soc ChemCom, 1992,662-664; J Org Chem, 1992,57:4232-4237; Tetrahedron Lett, 1982,23:2293-2296; Tetrahedron Lett, 1986,27:4961-4964; Tetrahedron Lett, 1988,29:1409-1412; Tetrahedron Lett, 1998, all reported the preparation method of 4-AA on the 39:7779-7782.
The raw material sources that have in the described method are had any problem, the chiral catalyst that the employing that has is very expensive, and the severe reaction conditions that has, cis-selectivity is not high, purifies for separation and brings difficulty.
Wherein utilize the chirality assistant agent to induce asymmetric Aldol condensation reaction can generate two chiral centres simultaneously, the cis-selectivity height, to excellent, and the chirality assistant agent realizes suitability for industrialized production gradually in the yield, for the industrial applications of this route is laid good basis.
Document J Org Chem, 1992,57:4243-4249 is to be the chirality assistant agent with (4S)-4-sec.-propyl thiazolidine-2-thio-ketone, introduces required chirality by the asymmetric Aldol condensation of assistant agent inductive.But the difficult preparation of thiazolidine-2-thio-ketone class prothetic group, the suitability for industrialized production that still is unrealized, so its application is subjected to certain restriction.
EP0774463 induces by the chirality assistant agent and generates needed chirality, and is loaded down with trivial details but its assistant agent of using prepares, and is unfavorable for suitability for industrialized production.
Figure S061B8008320061129D000022
Summary of the invention
One of technical issues that need to address of the present invention be open (2 ' S, 3 ' R, 4S)-3-[2 '-(N-replaces aminomethyl)-3 '-maloyl group]-4-substituted oxazole alkane-2-ketone derivatives.
That two of the technical issues that need to address of the present invention provide is above-mentioned (2 ' S, 3 ' R, 4S)-3-[2 '-(N-replaces aminomethyl)-3 '-maloyl group]-preparation method of 4-substituted oxazole alkane-2-ketone derivatives.
Of the present invention (2 ' S, 3 ' R, 4S)-3-[2 '-(N-replaces aminomethyl)-3 '-maloyl group]-4-substituted oxazole alkane-2-ketone derivatives is the compound with following general structure (I):
Wherein,
R 1, R 2Be (1) benzyl or substituted benzyl, the substituting group on the substituted benzyl phenyl ring be positioned at the neighbour,, contraposition, single replace or polysubstituted,, wherein substituting group is methoxyl group, nitro; (2)-COOR 4, R wherein 4Be alkyl, substituted alkyl, the benzyl of 1～4 carbon; (3)-COOCH 2C 6H 4R 5, R wherein 5Be nitro, methoxyl group, halogen; (4)-COR 6, R wherein 6Be H, the alkyl of 1～4 carbon, phenyl, xenyl, benzyl; (5)-COC (R 7) n, R wherein 7Be halogen, n is 1 or 2 or 3;
R 3Be benzyl, sec.-propyl or phenyl.
Preferably, R 1, R 2For to methoxy-benzyl, 3; 4-dimethoxy-benzyl, 3-methoxy-benzyl, 2-nitrobenzyl, 4-nitrobenzyl, methoxycarbonyl base, ethoxycarbonyl, 2; 2,2-trichlorine ethoxycarbonyl, uncle's fourth oxygen formyl radical, carbobenzoxy, to methoxyl group benzyloxy formyl radical, to the nitro carbobenzoxy, to bromobenzyl oxygen formyl radical, to benzyl chloride oxygen formyl radical, formyl radical, ethanoyl, chloracetyl, tribromo-acetyl base, trifluoroacetyl group, phenylacetyl, hydrocinnamoyl, benzoyl or to the phenyl benzoyl.
More preferably, R 1, R 2Be benzyl, benzoyl or carbobenzoxy; R 3Be benzyl.
Preferred formula (I) compound is (2 ' S; 3 ' R; 4S)-3-[2 '-(N-benzyl-N-carbobenzoxy-(Cbz)) aminomethyl-3 '-maloyl group]-4-Bian Ji oxazolidine-2-ketone, (2 ' S; 3 ' R; 4S)-3-[2 '-(N; the N-dibenzyl) aminomethyl-3 '-maloyl group]-4-Bian Ji oxazolidine-2-ketone, (2 ' S, 3 ' R, 4S)-3-[2 '-(N-benzyl-N-benzoyl) aminomethyl-3 '-maloyl group]-4-Bian Ji oxazolidine-2-ketone.
The preparation method of compound of the present invention (I) comprises the steps:
(1) N-replacement-3-Beta Alanine (IV) reacts with compound (V) under the activation of carboxyl activator, obtains compound (II).
Reaction expression is:
Figure S061B8008320061129D000041
(2) will have general structure and in organic solvent, under the effect of metal catalyst and alkali, carry out condensation reaction with acetaldehyde for the compound shown in (II), then by ordinary method as passing through recrystallization, column chromatography, the preparation thin-layer chromatography is collected purifying and is obtained product (I).
Reaction expression is:
Figure S061B8008320061129D000042
The employed organic solvent of two-step reaction is not particularly limited, as long as reaction or agents useful for same are not had side reaction, solvent for use can dissolve or solubilizing reaction thing to a certain extent, and suitable organic solvent comprises hydro carbons, as benzene or dimethylbenzene, toluene or alkane, halohydrocarbon; Ethers is as tetrahydrofuran (THF), ether, propyl ether, diox; Amides, N, dinethylformamide, N, the N-diethylformamide, N,N-dimethylacetamide etc., wherein preferred solvent is tetrahydrofuran (THF), toluene and methylene dichloride.
The temperature of reaction of two-step reaction can be in the scope of certain width, and precise dose is very unimportant to this reaction.Usually-100 ℃～150 ℃, be preferably-80 ℃～50 ℃.
Reaction times is preferably 0.5～24 hour usually because of solvent, temperature of reaction are different.
Employed carboxylic acid activating agent's character is unimportant in the above-mentioned chemical process (1), any can the activating carboxy acid and the activator of acid amides reaction all can be applicable to this reaction.Preferred reagent comprises: pivaloyl chloride, chloro-formic ester, carbodiimide such as dicyclohexylcarbodiimide, 4-Dimethylamino pyridine (DMAP) and thionyl chloride etc.
Used metal catalyst comprises titanium catalyst such as TiCl in the above-mentioned chemical process (2) 4, TiCl 3(OCH 3), TiCl 3(OC 2H 5), TiCl 3(OC 3H 7 n), TiCl 3(OC 3H 7 i), TiCl 3(OC 4H 9 n), TiCl 3(OC 4H 9 i), TiCl 3(OC 4H 9 s), TiCl 3(OC 4H 9 t), TiCl 2(OCH 3) 2, TiCl 2(OC 2H 5) 2, TiCl 2(OC 3H 7 n) 2, TiCl 2(OC 3H 7 i) 2, TiCl 2(OC 4H 9 n) 2Or TiCl (OC 3H 7 i) 3Zinc catalyst such as ZnCl 2Or ZnI 2Tin catalyst such as SnCl 2Or Sn (OTf) 2B catalyst is as (C 4H 9 n) 2BOTf.Mg catalyst such as Mg (OC 2H 5) 2, MgI 2Or MgClO 4Or the like.Tf represents trifluoromethanesulfonic acid base, C 3H 7 n, C 3H 7 i, C 4H 9 n, C 4H 9 i, C 4H 9 s, C 4H 9 tRepresent n-propyl respectively, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl.Preferred TiCl in these catalyzer 4Or TiCl (OC 3H 7 1) 3, (C 4H 9 n) 2BOTf or Sn (OTf) 2
Used alkali comprises secondary amine such as dimethylamine, diethylamine, Diisopropylamine, dicyclohexyl amine, methylphenylamine, piperidines, pyrroles, morpholine etc. in the above-mentioned chemical process (2); Tertiary amine such as diisopropylethylamine, diisopropyl methylamine, triethylamine, N, accelerine, N-ethylpiperidine, N-methylmorpholine, N-ethyl pyrrolidine etc.; Diamines such as N,N,N etc.Wherein preferred alkali is N,N,N, diisopropylethylamine, N-ethylpiperidine etc.
Of the present invention (2 ' S, 3 ' R, 4S)-3-[2 '-(N-replaces aminomethyl)-3 '-maloyl group]-4-substituted oxazole alkane-2-ketone derivatives is used to prepare the critical materials 4-AA of carbapenem antibiotic.
Preparation method of the present invention induces two chiral centres of the efficient introducing of asymmetric Aldol condensation by the chirality assistant agent, the domestic scale operation of progressive chirality assistant agent along with the epoch, price reduces greatly, other raw materials, reagent are cheap and easy to get, easy and simple to handle, method is reasonable, is fit to suitability for industrialized production, thereby has essential industry value on preparation 4-AA.
Embodiment
Below will describe the specific embodiment of the present invention, but embodiment does not limit protection scope of the present invention by embodiment.
Embodiment 1
(1) (4S)-3-[3 '-(N-benzyl-N-carbobenzoxy amino) propionyl]-preparation of 4-Bian Ji oxazolidine-2-ketone:
Be equipped with in the 1000ml four-hole round-bottomed flask of magnetic stirrer, thermometer one, add 40g N-benzyl-N-carbobenzoxy-3-alanine, 34.2ml triethylamine and 500ml tetrahydrofuran (THF).After being cooled to-20 ℃, drip pivaloyl chloride 15.7ml, under this temperature, stirred 2 hours.Add Lithium chloride (anhydrous) 5.42g then, S-4-Bian Ji oxazolidine-2-ketone 17.4g.Rise to stirred overnight at room temperature after adding.Be spin-dried for tetrahydrofuran (THF), add 200ml water and 300ml ethyl acetate, also water, saturated sodium carbonate are washed organic layer, anhydrous magnesium sulfate drying respectively behind the separatory.Recrystallization or column chromatography get title compound 48.3g.
1H?NMR(400MHz，CDCl 3)2.71(1H，m)，3.13-3.26(3H，m)，3.65(2H，s)，4.12(2H，s)，4.55(3H，t)，5.19(2H，s)，7.16-7.33(15H，m)；
MS：(M+1) +473.5
(2) (2 ' S, 3 ' R, 4S)-3-[2 '-(N-benzyl-N-carbobenzoxy aminomethyl)-3 '-maloyl group]-preparation of 4-Bian Ji oxazolidine-2-ketone:
Be equipped with in the 250ml four-hole round-bottomed flask of magnetic stirrer, thermometer one; add 20g (4S)-3-[3 '-(N-benzyl-N-carbobenzoxy amino) propionyl under the nitrogen protection condition]-4-Bian Ji oxazolidine-2-ketone and 160ml methylene dichloride; be cooled to 0 ℃, to wherein dripping titanium tetrachloride 6.51ml.Drip N,N,N 17.73ml behind 15 clocks.After 1 hour reaction solution is cooled to-78 ℃, to wherein dripping acetaldehyde 2.86ml, reaction is 2 hours under this temperature.Drip saturated ammonium chloride 100ml, separatory, water layer ethyl acetate extraction (100ml * 3) merges organic layer, dried over mgso, the filtration back is steamed and is desolventized, and silica gel column chromatography separates to such an extent that product 13.56 restrains.
1H?NMR(400MHz，CDCl 3)1.18(3H，d)，2.52(1H，s)，3.10(1H，s)，3.32(1H，s)，3.62(1H，d)，3.82(1H，s)，4.15(3H，m)，4.56-4.68(4H，m)，5.19(2H，m)，7.16-7.33(15H，m)；
MS：(M+1) +517.4
Embodiment 2
(1) (4S)-3-[3 '-(N, N-dibenzyl amino) propionyl]-preparation of 4-benzyl-oxazolidines-2-ketone:
Be equipped with in the 100ml four-hole round-bottomed flask of magnetic stirrer, thermometer one, add 5g N, N-dibenzyl-3-alanine, 20ml methylene dichloride and 4.48ml triethylamine, stirring at room 10min.Stirring at room is 3 hours behind the dropping pivaloyl chloride 2.27ml.Add 3.27g S-4-Bian Ji oxazolidine-2-ketone, 0.3g4-Dimethylamino pyridine and 5mlN, dinethylformamide refluxed 10 hours.Water, saturated sodium bicarbonate, saturated common salt are washed organic layer, anhydrous magnesium sulfate drying respectively.Recrystallization or column chromatography get titleization and thing 5.45g.
1H?NMR(400MHz，CDCl 3)2.68(1H，m)，2.92(2H，m)，3.17(2H，m)，3.28(1H，dd)，3.64(4H，m)，4.07(2H，t)，4.58(1H，m)，7.16-7.36(15H，m)；
MS：(M+1) +429.2
(2) (2 ' S, 3 ' R, 4S)-3-[2 '-(N, N-dibenzyl aminomethyl)-3 '-maloyl group]-preparation of 4-Bian Ji oxazolidine-2-ketone:
Be equipped with in the 250ml four-hole round-bottomed flask of magnetic stirrer, thermometer one; add 20g (4S)-3-[3 '-(N under the nitrogen protection condition; the N-dibenzyl amino) propionyl]-4-benzyl-oxazolidines-2-ketone and the anhydrous ethylene dichloride of 160ml; be cooled to 0 ℃, to wherein dripping titanium tetrachloride 9.96ml.Drip N,N,N 17.5ml after 15 minutes.To wherein dripping acetaldehyde 5.3ml, reaction is 2 hours under this temperature after 1 hour.Drip saturated ammonium chloride 100ml, separatory, water layer ethyl acetate extraction (100ml * 3) merges organic layer, dried over mgso, the filtration back is steamed and is desolventized, and silica gel column chromatography separates to such an extent that product 8.82 restrains.
1H?NMR(400MHz，CDCl 3)1.12(3H，d)，2.74(2H，m)，3.01(1H，t)，3.23(3H，m)，3.64-4.32(6H，m)，4.62(1H，m)，7.06-7.31(15H，m)；
MS：(M+1) +473.2
Embodiment 3
(1) (4S)-3-[3 '-(N-benzyl-N-benzoyl-amido) propionyl]-preparation of 4-Bian Ji oxazolidine-2-ketone:
Be equipped with in the 1000ml four-hole round-bottomed flask of magnetic stirrer, thermometer one, add 17.96gN-benzyl-N-benzoyl-3-alanine, 13.25ml triethylamine and 500ml tetrahydrofuran (THF).After being cooled to-78 ℃, drip pivaloyl chloride 9.34ml, under this temperature, stirred 2 hours.Add Lithium chloride (anhydrous) 3.5g then, S-4-Bian Ji oxazolidine-2-ketone 12.36g.Rise to stirred overnight at room temperature after adding.Be spin-dried for tetrahydrofuran (THF), add 200ml water and 300ml ethyl acetate, and water, saturated sodium carbonate washed organic layer respectively, anhydrous magnesium sulfate drying.Recrystallization or column chromatography get title compound 21.9g.
1H?NMR(400MHz，CDCl 3)2.75(1H，s)，3.18-3.32(3H，d)，3.74-3.86(2H，d)，4.14(2H，t)，4.60(3H，s)，7.18-7.44(15H，m)；
MS：(M+1) +443.4
(2) (2 ' S, 3 ' R, 4S)-3-[2 '-(N-benzyl-N-benzoyl aminomethyl)-3 '-maloyl group]-preparation of 4-Bian Ji oxazolidine-2-ketone:
Be equipped with in three mouthfuls of round-bottomed flasks of 100ml of magnetic stirrer, thermometer one; add 3g (4S)-3-[3 '-(N-benzyl-N-benzoyl-amido) propionyl under the nitrogen protection condition]-4-Bian Ji oxazolidine-2-ketone and 40ml methylene dichloride; be cooled to-78 ℃, to wherein dripping 1.9ml (C 4H 9 n) 2BOTf and 1.13ml triethylamine.To wherein dripping acetaldehyde 0.421ml, reaction is 1 hour under this temperature after 20 minutes, is warming up to-40 ℃ of reactions 30 minutes.Drip 30ml saturated ammonium chloride and 20ml methyl alcohol.Add the mixing solutions (volume ratio 2:1) of 60ml methyl alcohol and hydrogen peroxide then, be spin-dried for solvent, water layer merges organic layer with extracted with diethyl ether (100ml * 3), and dried over mgso is filtered the back and steamed and desolventize, silica gel column chromatography separate product 2.5g.
1H?NMR(400MHz，CDCl 3)1.30(3H，m)，2.74(1H，m)，3.33(1H，s)，3.69(2H，t)，4.19(5H，m)，4.57(1H，d)，4.72(2H，m)，7.21-7.49(15H，m)；
MS：(M+1) +487.5
Embodiment 4
(1) (4S)-3-[3 '-(N-benzyl-uncle's N-fourth oxygen formyl radical amino) propionyl]-preparation of 4-Bian Ji oxazolidine-2-ketone:
Be equipped with in the 250ml four-hole round-bottomed flask of magnetic stirrer, thermometer one, add 2.8g N-benzyl-uncle's N-fourth oxygen formyl radical-3-alanine, 3.5ml triethylamine and 100ml tetrahydrofuran (THF).After being cooled to-78 ℃, drip pivaloyl chloride 1.5ml, under this temperature, stirred 2 hours.Add Lithium chloride (anhydrous) 0.5g then, S-4-Bian Ji oxazolidine-2-ketone 1.8g.Rise to stirred overnight at room temperature after adding.Be spin-dried for tetrahydrofuran (THF), add 200ml water and 300ml ethyl acetate, and water, saturated sodium carbonate washed organic layer respectively, anhydrous magnesium sulfate drying.Recrystallization or column chromatography get title compound 3.4g.
1H?NMR(400MHz，CDCl 3)1.51(9H，m)，2.70(1H，m)，3.15-3.30(3H，m)，3.70(2H，m)，4.14(2H，m)，4.60(3H，s)，7.20-7.53(10H，m)；
MS：(M+1) +439.5
(2) (2 ' S, 3 ' R, 4S)-3-[2 '-(N-benzyl-uncle's N-fourth oxygen formyl radical aminomethyl)-3 '-maloyl group]-preparation of 4-Bian Ji oxazolidine-2-ketone:
Be equipped with in three mouthfuls of round-bottomed flasks of 100ml of magnetic stirrer, thermometer one; add 4.4g (4S)-3-[3 '-(N-benzyl-uncle's N-fourth oxygen formyl radical amino) propionyl under the nitrogen protection condition]-4-Bian Ji oxazolidine-2-ketone and 40ml methylene dichloride; be cooled to 0 ℃; to wherein dripping the 1.2ml titanium tetrachloride; react and drip 3.7ml N after 5 minutes; N, N ', N '-Tetramethyl Ethylene Diamine.After one hour, be cooled to-78 ℃ and drip acetaldehyde 0.62ml in reaction solution, reaction is 1 hour under this temperature, is warming up to-40 ℃ of reactions 30 minutes.Drip the cancellation of 30ml saturated ammonium chloride.Water layer merges organic layer with extracted with diethyl ether (100ml * 3), and dried over mgso is filtered the back and steamed and desolventize, silica gel column chromatography separate product 3.1g.
1H?NMR(400MHz，CDCl 3)1.20(3H，m)，1.42(9H，m)，2.72(1H，m)，3.34(1H，m)，3.69(2H，m)，4.18-4.35(4H，m)，4.57(2H，m)，4.72(2H，m)，7.19-7.39(10H，m)；
MS：(M+1) +483.5
Embodiment 5
(1) (4S)-3-[3 '-(N, N-dibenzyl amino) propionyl]-preparation of 4-phenyl-oxazolidines-2-ketone:
Be equipped with in the 100ml four-hole round-bottomed flask of magnetic stirrer, thermometer one, add 5g N, N-dibenzyl-3-alanine, 20ml methylene dichloride and 4.48ml triethylamine, stirring at room 10min.Stirring at room is 3 hours behind the dropping pivaloyl chloride 2.27ml.Add 3.03g S-4-Ben Ji oxazolidine-2-ketone, 0.3g4-Dimethylamino pyridine and 5ml N, dinethylformamide refluxed 10 hours.Water, saturated sodium bicarbonate, saturated common salt are washed organic layer, anhydrous magnesium sulfate drying respectively.Recrystallization or column chromatography get titleization and thing 5.45g.
1H?NMR(400MHz，CDCl 3)2.93(2H，m)，3.15(2H，m)，3.61(4H，m)，4.43(2H，m)，4.72(1H，m)，7.10-7.31(15H，m)；
MS：(M+1) +415.5
(2) (2 ' S, 3 ' R, 4S)-3-[2 '-(N, N-dibenzyl aminomethyl)-3 '-maloyl group]-preparation of 4-Ben Ji oxazolidine-2-ketone:
Be equipped with in the 250ml four-hole round-bottomed flask of magnetic stirrer, thermometer one; add 20g (4S)-3-[3 '-(N under the nitrogen protection condition; the N-dibenzyl amino) propionyl]-4-phenyl-oxazolidines-2-ketone and the anhydrous ethylene dichloride of 160ml; be cooled to 0 ℃, to wherein dripping titanium tetrachloride 6.9ml.Drip N,N,N 18.1ml after 15 minutes.To wherein dripping acetaldehyde 4.1ml, reaction is 2 hours under this temperature after 1 hour.Drip saturated ammonium chloride 100ml, separatory, water layer ethyl acetate extraction (100ml * 3) merges organic layer, dried over mgso, the filtration back is steamed and is desolventized, and silica gel column chromatography separates to such an extent that product 14.2 restrains.
1H?NMR(400MHz，CDCl 3)1.12(3H，d)，2.74(2H，m)，3.01(1H，m)，3.61(5H，m)，3.98(3H，m)4.62(1H，m)，7.06-7.31(15H，m)；
MS：(M+1) +459.6
Embodiment 6
(1) (4S)-3-[3 '-(N-benzyl-N-carbobenzoxy amino) propionyl]-preparation of 4-Yi Bing Ji oxazolidine-2-ketone:
Be equipped with in the 100ml four-hole round-bottomed flask of magnetic stirrer, thermometer one, add 4g N-benzyl-N-carbobenzoxy-3-alanine, 3.42ml triethylamine and 50ml tetrahydrofuran (THF).After being cooled to-20 ℃, drip pivaloyl chloride 1.57ml, under this temperature, stirred 2 hours.Add Lithium chloride (anhydrous) 0.54g then, S-4-Yi Bing Ji oxazolidine-2-ketone 1.8g.Rise to stirred overnight at room temperature after adding.Be spin-dried for tetrahydrofuran (THF), add 50ml water and 100ml ethyl acetate, also water, saturated sodium carbonate are washed organic layer, anhydrous magnesium sulfate drying respectively behind the separatory.Recrystallization or column chromatography get title compound 4.33g.
1H?NMR(400MHz，CDCl 3)1.01(6H，m)，2.22-2.57(1H，m)，3.15-3.26(2H，m)，3.62(2H，s)，4.12(2H，s)，4.3-4.55(3H，m)，5.19(2H，s)，7.16-7.33(15H，m)；
MS：(M+1) +425.5
(2) (2 ' S, 3 ' R, 4S)-3-[2 '-(N-benzyl-N-carbobenzoxy aminomethyl)-3 '-maloyl group]-preparation of 4-Yi Bing Ji oxazolidine-2-ketone:
Be equipped with in the 250ml four-hole round-bottomed flask of magnetic stirrer, thermometer one; add 20g (4S)-3-[3 '-(N-benzyl-N-carbobenzoxy amino) propionyl under the nitrogen protection condition]-4-Yi Bing Ji oxazolidine-2-ketone and 160ml methylene dichloride; be cooled to 0 ℃, to wherein dripping titanium tetrachloride 5.68ml.Drip N,N,N 17.6ml behind 15 clocks.After 1 hour reaction solution is cooled to-78 ℃, to wherein dripping acetaldehyde 2.86ml, reaction is 2 hours under this temperature.Drip saturated ammonium chloride 100ml, separatory, water layer ethyl acetate extraction (100ml * 3) merges organic layer, dried over mgso, the filtration back is steamed and is desolventized, and silica gel column chromatography separates to such an extent that product 13.56 restrains.
1H?NMR(400MHz，CDCl 3)1.18(3H，d)，2.52(1H，s)，3.10(1H，s)，3.32(1H，s)，3.62(1H，d)，3.82(1H，s)，4.15(3H，m)，4.56-4.68(4H，m)，5.19(2H，m)，7.16-7.33(15H，m)；
MS：(M+1) +469.55
Embodiment 7
(1) (4S)-3-[3 '-(N-benzyl-N-carbobenzoxy amino) propionyl]-preparation of 4-Bian Ji oxazolidine-2-ketone:
Be equipped with in the 1000ml four-hole round-bottomed flask of magnetic stirrer, thermometer one, add 40g N-benzyl-N-carbobenzoxy-3-alanine, 34.2ml triethylamine and 500ml tetrahydrofuran (THF).After being cooled to-20 ℃, drip pivaloyl chloride 15.7ml, under this temperature, stirred 2 hours.Add Lithium chloride (anhydrous) 5.42g then, S-4-Bian Ji oxazolidine-2-ketone 17.4g.Rise to stirred overnight at room temperature after adding.Be spin-dried for tetrahydrofuran (THF), add 200ml water and 300ml ethyl acetate, also water, saturated sodium carbonate are washed organic layer, anhydrous magnesium sulfate drying respectively behind the separatory.Recrystallization or column chromatography get title compound 48.3g.
1H?NMR(400MHz，CDCl 3)2.71(1H，m)，3.13-3.26(3H，m)，3.65(2H，s)，4.12(2H，s)，4.55(3H，t)，5.19(2H，s)，7.16-7.33(15H，m)；
MS：(M+1) +473.5
(2) (2 ' S, 3 ' R, 4S)-3-[2 '-(N-benzyl-N-carbobenzoxy aminomethyl)-3 '-maloyl group]-preparation of 4-Bian Ji oxazolidine-2-ketone:
One 21.2gSn (OTf) is housed in the 250ml four-hole round-bottomed flask of magnetic stirrer, thermometer 2Be cooled to-78 ℃ with 7.2g N-ethylpiperidine, 60ml methylene dichloride.To wherein dripping 20g (4S)-3-[3 '-(N-benzyl-N-carbobenzoxy amino) propionyl]-the 100ml dichloromethane solution of 4-Bian Ji oxazolidine-2-ketone, stir and drip acetaldehyde 2.86ml after 15 minutes.Continue reaction adding in 1 hour saturated ammonium chloride 100ml, filter white precipitate, separatory, water layer dichloromethane extraction (100ml * 3) merges organic layer, and dried over mgso is filtered the back steaming and is desolventized, and silica gel column chromatography separates to such an extent that product 12.21 restrains.
1H?NMR(400MHz，CDCl 3)1.18(3H，d)，2.52(1H，s)，3.10(1H，s)，3.32(1H，s)，3.62(1H，d)，3.82(1H，s)，4.15(3H，m)，4.56-4.68(4H，m)，5.19(2H，m)，7.16-7.33(15H，m)；
MS：(M+1) +517.4
Embodiment 8
(1) (4S)-3-[3 '-(N, N-dibenzyl amino) propionyl]-preparation of 4-benzyl-oxazolidines-2-ketone:
Be equipped with in the 100ml four-hole round-bottomed flask of magnetic stirrer, thermometer one, add 5g N, N-dibenzyl-3-alanine, 20ml methylene dichloride and 4.48ml triethylamine, stirring at room 10min.Stirring at room is 3 hours behind the dropping pivaloyl chloride 2.27ml.Add 3.27g S-4-Bian Ji oxazolidine-2-ketone, 0.3g4-Dimethylamino pyridine and 5mlN, dinethylformamide refluxed 10 hours.Water, saturated sodium bicarbonate, saturated common salt are washed organic layer, anhydrous magnesium sulfate drying respectively.Recrystallization or column chromatography get titleization and thing 5.45g.
1H?NMR(400MHz，CDCl 3)2.68(1H，m)，2.92(2H，m)，3.17(2H，m)，3.28(1H，dd)，3.64(4H，m)，4.07(2H，t)，4.58(1H，m)，7.16-7.36(15H，m)；
MS：(M+1) +429.2
(2) (2 ' S, 3 ' R, 4S)-3-[2 '-(N, N-dibenzyl aminomethyl)-3 '-maloyl group]-preparation of 4-Bian Ji oxazolidine-2-ketone:
Be equipped with in the 250ml four-hole round-bottomed flask of magnetic stirrer, thermometer one; add 20g (4S)-3-[3 '-(N under the nitrogen protection condition; the N-dibenzyl amino) propionyl]-4-benzyl-oxazolidines-2-ketone and the anhydrous ethylene dichloride of 160ml; be cooled to 0 ℃, to wherein dripping titanium tetrachloride 9.96ml.Drip diisopropylethylamine 9.7ml after 15 minutes.To wherein dripping acetaldehyde 5.3ml, reaction is 2 hours under this temperature after 1 hour.Drip saturated ammonium chloride 100ml, separatory, water layer ethyl acetate extraction (100ml * 3) merges organic layer, dried over mgso, the filtration back is steamed and is desolventized, and silica gel column chromatography separates to such an extent that product 8.42 restrains.
1H?NMR(400MHz，CDCl 3)1.12(3H，d)，2.74(2H，m)，3.01(1H，t)，3.23(3H，m)，3.64-4.32(6H，m)，4.62(1H，m)，7.06-7.31(15H，m)；
MS：(M+1) +473.2
Embodiment 9
(1) (4S)-3-[3 '-(N, N-dibenzyl amino) propionyl]-preparation of 4-benzyl-oxazolidines-2-ketone:
Be equipped with in the 100ml four-hole round-bottomed flask of magnetic stirrer, thermometer one, add 5g N, N-dibenzyl-3-alanine, 20ml methylene dichloride and 4.48ml triethylamine, stirring at room 10min.Stirring at room is 3 hours behind the dropping pivaloyl chloride 2.27ml.Add 3.27g S-4-Bian Ji oxazolidine-2-ketone, 0.3g4-Dimethylamino pyridine and 5mlN, dinethylformamide refluxed 10 hours.Water, saturated sodium bicarbonate, saturated common salt are washed organic layer, anhydrous magnesium sulfate drying respectively.Recrystallization or column chromatography get titleization and thing 5.45g.
1H?NMR(400MHz，CDCl 3)2.68(1H，m)，2.92(2H，m)，3.17(2H，m)，3.28(1H，dd)，3.64(4H，m)，4.07(2H，t)，4.58(1H，m)，7.16-7.36(15H，m)；
MS：(M+1) +429.2
(2) (2 ' S, 3 ' R, 4S)-3-[2 '-(N, N-dibenzyl aminomethyl)-3 '-maloyl group]-preparation of 4-Bian Ji oxazolidine-2-ketone:
Be equipped with in the 250ml four-hole round-bottomed flask of magnetic stirrer, thermometer one; add 20g (4S)-3-[3 '-(N under the nitrogen protection condition; the N-dibenzyl amino) propionyl]-4-benzyl-oxazolidines-2-ketone and 160ml anhydrous diethyl ether, be cooled to 0 ℃, to wherein dripping titanium tetrachloride 9.96ml.Drip diisopropylethylamine 9.7ml after 15 minutes.To wherein dripping acetaldehyde 5.3ml, reaction is 2 hours under this temperature after 1 hour.Drip saturated ammonium chloride 100ml, separatory, water layer ethyl acetate extraction (100ml * 3) merges organic layer, dried over mgso, the filtration back is steamed and is desolventized, and silica gel column chromatography separates to such an extent that product 7.8 restrains.
1H?NMR(400MHz，CDCl 3)2.68(1H，m)，2.92(2H，m)，3.17(2H，m)，3.28(1H，dd)，3.64(4H，m)，4.07(2H，t)，4.58(1H，m)，7.16-7.36(15H，m)；
MS：(M+1) +429.2
Embodiment 10
(1) (4S)-3-[3 '-(N-benzyl-N-benzoyl-amido) propionyl]-preparation of 4-Bian Ji oxazolidine-2-ketone:
Be equipped with in the 1000ml four-hole round-bottomed flask of magnetic stirrer, thermometer one, add 17.96gN-benzyl-N-benzoyl-3-alanine, 13.25ml triethylamine and 500ml tetrahydrofuran (THF).After being cooled to-78 ℃, drip pivaloyl chloride 9.34ml, under this temperature, stirred 2 hours.Add Lithium chloride (anhydrous) 3.5g then, S-4-Bian Ji oxazolidine-2-ketone 12.36g.Rise to stirred overnight at room temperature after adding.Be spin-dried for tetrahydrofuran (THF), add 200ml water and 300ml ethyl acetate, and water, saturated sodium carbonate washed organic layer respectively, anhydrous magnesium sulfate drying.Recrystallization or column chromatography get title compound 21.9g.
1H?NMR(400MHz，CDCl 3)2.75(1H，s)，3.18-3.32(3H，d)，3.74-3.86(2H，d)，4.14(2H，t)，4.60(3H，s)，7.18-7.44(15H，m)；
MS：(M+1) +443.4
(3) (2 ' S, 3 ' R, 4S)-3-[2 '-(N-benzyl-N-benzoyl aminomethyl)-3 '-maloyl group]-preparation of 4-Bian Ji oxazolidine-2-ketone:
Be equipped with in three mouthfuls of round-bottomed flasks of 100ml of magnetic stirrer, thermometer one; add 3g (4S)-3-[3 '-(N-benzyl-N-benzoyl-amido) propionyl under the nitrogen protection condition]-4-Bian Ji oxazolidine-2-ketone and 40ml tetrahydrofuran (THF); be cooled to 0 ℃, to wherein dripping 1.95g TiCl (OC 3H 7 i) 3With diisopropylethylamine 1.4ml.To wherein dripping acetaldehyde 0.421ml, reaction is 1 hour under this temperature after 20 minutes, is warming up to-40 ℃ of reactions 30 minutes.Drip the 30ml saturated ammonium chloride, be spin-dried for solvent, water layer merges organic layer with extracted with diethyl ether (100ml * 3), and dried over mgso is filtered the back and steamed and desolventize, silica gel column chromatography separate product 1.65g.
1H?NMR(400MHz，CDCl 3)1.30(3H，m)，2.74(1H，m)，3.33(1H，s)，3.69(2H，t)，4.19(5H，m)，4.57(1H，d)，4.72(2H，m)，7.21-7.49(15H，m)；
MS：(M+1) +487.5

Claims (12)

1. the compound of following general formula (I):
Figure FSB00000226112800011
Wherein,
R 1, R 2Be (1) benzyl or substituted benzyl, the substituting group on the substituted benzyl phenyl ring be positioned at the neighbour,, contraposition, single replace or polysubstituted,, wherein substituting group is methoxyl group, nitro; (2)-COOR 4, R wherein 4Be alkyl, the benzyl of 1～4 carbon; (3)-COOCH 2C 6H 4R 5, R wherein 5Be nitro, methoxyl group, halogen; (4)-COR 6, R wherein 6Be H, the alkyl of 1～4 carbon, phenyl, xenyl, benzyl; (5)-COC (R 7) n, R wherein 7Be halogen, n is 3; (6) 2,2,2-trichlorine ethoxycarbonyl; R 3Be benzyl, sec.-propyl or phenyl.
2. compound as claimed in claim 1, wherein R 1, R 2For to methoxy-benzyl, 3,4-dimethoxy-benzyl, 3-methoxy-benzyl, 2-nitrobenzyl, 4-nitrobenzyl, methoxycarbonyl base, ethoxycarbonyl, uncle's fourth oxygen formyl radical, carbobenzoxy, to methoxyl group benzyloxy formyl radical, to the nitro carbobenzoxy, to bromobenzyl oxygen formyl radical, to benzyl chloride oxygen formyl radical, formyl radical, ethanoyl, chloracetyl, tribromo-acetyl base, trifluoroacetyl group, phenylacetyl, hydrocinnamoyl, benzoyl or to the phenyl benzoyl.
3. compound as claimed in claim 2, wherein R 1, R 2Be benzyl, benzoyl or carbobenzoxy; R 3Be benzyl.
4. compound as claimed in claim 3; wherein this compound is (2 ' S; 3 ' R; 4S)-3-[2 '-(N-benzyl-N-carbobenzoxy aminomethyl)-3 '-maloyl group]-4-Bian Ji oxazolidine-2-ketone; (2 ' S; 3 ' R; 4S)-3-[2 '-(N; N-dibenzyl aminomethyl)-3 '-maloyl group]-4-Bian Ji oxazolidine-2-ketone; (2 ' S; 3 ' R; 4S)-3-[2 '-(N-benzyl-N-benzoyl aminomethyl)-3 '-maloyl group]-4-Bian Ji oxazolidine-2-ketone; (2 ' S; 3 ' R; 4S)-3-[2 '-(N-benzyl-uncle's N-fourth oxygen formyl radical aminomethyl)-3 '-maloyl group]-4-Bian Ji oxazolidine-2-ketone; (2 ' S; 3 ' R; 4S)-3-[2 '-(N; N-dibenzyl aminomethyl)-3 '-maloyl group]-4-Ben Ji oxazolidine-2-ketone; (2 ' S, 3 ' R, 4S)-3-[2 '-(N-benzyl-N-carbobenzoxy aminomethyl)-3 '-maloyl group]-4-Yi Bing Ji oxazolidine-2-ketone.
5. the preparation method of the arbitrary described compound of claim 1-4, it is characterized in that, this method comprises the steps: that with having general structure be that the compound shown in the formula (II) obtains product (I) with the acetaldehyde condensation reaction in organic solvent under the effect of metal catalyst and alkali
Figure FSB00000226112800021
Wherein, R 1, R 2And R 3Definition as described in one of claim 1～4,
Wherein, described metal catalyst is TiCl 4, TiCl 3(OCH 3), TiCl 3(OC 2H 5), TiCl 3(OC 3H 7 n), TiCl 3(OC 3H 7 i), TiCl 3(OC 4H 9 n), TiCl 3(OC 4H 9 i), TiCl 3(OC 4H 9 s), TiCl 3(OC 4H 9 t), TiCl 2(OCH 3) 2, TiCl 2(OC 2H 5) 2, TiCl 2(OC 3H 7 n) 2, TiCl 2(OC 3H 7 i) 2, TiCl 2(OC 4H 9 n) 2, TiCl (OC 3H 7 i) 3, ZnCl 2, ZnI 2, SnCl 2, Sn (OTf) 2, (C 4H 9 n) 2BOTf, Mg (OC 2H 5) 2, MgI 2Or MgClO 4
6. method as claimed in claim 5 is characterized in that, described catalyzer is TiCl (OC 3H 7 i) 3, TiCl 4, (C 4H 9 n) 2BOTf or Sn (OTf) 2
7. method as claimed in claim 5, it is characterized in that, described alkali is dimethylamine, diethylamine, Diisopropylamine, dicyclohexyl amine, methylphenylamine, piperidines, pyrroles, morpholine, diisopropylethylamine, diisopropyl methylamine, triethylamine, N, accelerine, N-ethylpiperidine, N-methylmorpholine, N-ethyl pyrrolidine or N, N, N ', N '-Tetramethyl Ethylene Diamine.
8. method as claimed in claim 7 is characterized in that, described alkali is N,N,N or diisopropylethylamine.
9. method as claimed in claim 5 is characterized in that, described organic solvent is benzene, dimethylbenzene, toluene, alkane, halohydrocarbon, tetrahydrofuran (THF), ether, propyl ether, diox, N, dinethylformamide, N, N-diethylformamide or N,N-dimethylacetamide.
10. method as claimed in claim 9 is characterized in that, described organic solvent is tetrahydrofuran (THF) or methylene dichloride.
11. method as claimed in claim 5 is characterized in that, the temperature of reaction of described method is-100 ℃ to 150 ℃, and the reaction times is 0.5～24 hour.
12. method as claimed in claim 11 is characterized in that, described temperature of reaction is-80 ℃～50 ℃.
CN2006101180083A 2006-11-06 2006-11-06 (2'S,3'R,4S)-3-[2'-(N-substituted aminomethyl)-3'-hydroxy butyryl]-4-substituted oxazolidin-2-ketone derivative and preparation method thereof Active CN101177416B (en)

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Publication number Priority date Publication date Assignee Title
EP0167154A1 (en) * 1984-07-05 1986-01-08 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Process for preparing 4-acetoxy-3-hydroxyethylazetizin-2-one derivatives
EP0774463A1 (en) * 1995-11-17 1997-05-21 Tanabe Seiyaku Co., Ltd. Process for preparing acetoxyazetidinone derivative and intermediates thereof
WO1998007691A1 (en) * 1996-08-24 1998-02-26 Choongwae Pharmaceutical Co., Ltd. Process for stereoselective preparation of trans-azetidinones

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0167154A1 (en) * 1984-07-05 1986-01-08 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Process for preparing 4-acetoxy-3-hydroxyethylazetizin-2-one derivatives
EP0774463A1 (en) * 1995-11-17 1997-05-21 Tanabe Seiyaku Co., Ltd. Process for preparing acetoxyazetidinone derivative and intermediates thereof
WO1998007691A1 (en) * 1996-08-24 1998-02-26 Choongwae Pharmaceutical Co., Ltd. Process for stereoselective preparation of trans-azetidinones

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Yoshimitsu Nagao,Yunosuke Nagase et al.β-Lactams. 3. Asymmetric Total Synthesis of New Non-Natural1β-Methylcarbapenems Exhibiting StrongAntimicrobialActivities andStability against Human RenalDehydropeptidase-I.J. Org.Chem.57.1992,574243-4249. *

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