CN1927853A - Preparation method of racemic homocitric acid lactone - Google Patents
Preparation method of racemic homocitric acid lactone Download PDFInfo
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- CN1927853A CN1927853A CN 200610122344 CN200610122344A CN1927853A CN 1927853 A CN1927853 A CN 1927853A CN 200610122344 CN200610122344 CN 200610122344 CN 200610122344 A CN200610122344 A CN 200610122344A CN 1927853 A CN1927853 A CN 1927853A
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Abstract
The present invention relates to homocitric lactone, and is especially the simple large scale process of preparing racemic homocitric lactone with facile cheap 2-keto glutaric ester as material. The preparation process includes the reaction of 2-keto glutaric ester with negative ion in solvent, extraction, concentration and chromatographic column purification to form one intermediate compound; and the refluxing of the intermediate compound in formic acid, acetic acid and/or trifluoroacetic acid to obtain homocitric lactone. The negative ion is formed with one kind of ester selected from ethyl acetate, methyl acetate and tert-butyl acetate, and one kind of alkali selected from hexamethyl disilicoamido lithium formed with n-butyl lithium and hexamethyl disilane and diisopropylamino lithium formed with n-butyl lithium and diisopropylamine.
Description
Technical field
The present invention relates to a kind of homocitric acid lactone, especially a kind of is raw material with the 2-oxopentanedioic acid ester, can be compactly, the method for scale preparation racemic homocitric acid lactone.
Background technology
Homocitric acid (Homocitric acid) is important biochemical reagents, and it is the important intermediate of fungi and Euglena biosynthesizing Methionin, is considered to the potential antibacterials.Simultaneously homocitric acid plays important effect in nitrogenase catalysis nitrogen is reduced to the process of ammonia.The quantity that adopts at present the synthetic homocitric acid of enzyme process generally all in the hundreds of milligram, make that the price of homocitric acid is very expensive (〉=1000 dollars/g), and the whole world has only a company that sale is arranged, this has greatly limited relevant research.Therefore, development is succinct, particularly important can seem for the method for macro preparation homocitric acid.
(J.Org.Chem. such as Biellmann in 1996; 1996; 61; be raw material 1822-1824), at first utilize special valeral that its protection is (S)-2-tertiary butyl-5-methylene radical-1,3-dioxolane-4-ketone with L-lactic acid; addition reaction obtains the pure intermediate of high mapping through Unsymmetrical Diels-Alder Reaction Product then; then by ozonize-oxidation, esterification, go polystep reactions such as protection, finally obtain the homocitric acid lactone of (R)-configuration, the total recovery of reaction is 3.0%.Utilize same way, can synthesize the homocitric acid lactone that obtains (S)-configuration from the L-Serine.But this synthetic route overall yield is low, and practical value is not high.
(Tetrahedron Asymmetry such as Russell in 1997; 1997; 8; 3379-3382) with the citric acid be raw material; at first obtain racemic 2-(4-(2-methoxyl group-2-oxoethyl)-5-oxo-1 by three-step reaction; the 3-dioxolanyl)-and acetate, reset, go polystep reaction such as protection to obtain (R)-Gao lemon lactone then by (S)-phenylethylamine kinetic resolution, Arndt-Eistert reaction, Wolff.Total recovery is 5.61%.This route steps is long, complex operation, and practicality is not strong.
Lee in 1998 increase spring etc. (Molecules, 1998,3,31-34) with the monoethyl malonate be raw material, synthesized important intermediate 3-oxo-hexanodioic acid methyl ethyl ester by esterification, condensation, rearrangement three-step reaction.The addition by prussic acid then, hydrolysis, vitriol oil effect dehydration and obtain racemic homocitric acid lactone, total recovery 41.9% down.This route reaction step is shorter relatively, and certain synthetic value is arranged, but must use the potassium cyanide of severe toxicity in the reaction process.
(the Tetrahedron Lett of Palmer group in 2000; 2000; 41,9209-9212) from the D-oxysuccinic acid, at first utilize synthetic special valeral that oxysuccinic acid protection is obtained crucial intermediate; pass through electrophilic substitution then; hydroboration, protection is gone in the PDC oxidation; polystep reactions such as basic hydrolysis obtain the homocitric acid trisodium salt of (R)-configuration, and the total recovery of reaction is 12.0%.This route complex operation, practicality is not high.
Lopp group in 2004 (Tetrahedron, 2004,60,9081-9084) reported by the method for spirocyclic compound through brief path of preparing homocitric acid lactone.The author is with spirocyclic compound oxidation in alkalinity potassium permanganate, and acidifying promptly gets the homocitric acid lactone then, overall yield 74%.Although it is very succinct that this route seems, the preparation of crucial intermediate spirocyclic compound trouble does not possess practical value.
Young group in 2005 (Tetrahedron Lett.2005,46,2093-2096) reported that with (-)-quinic acid derivative be the method for raw material through the synthetic homocitric acid derivative of 4 steps reaction.The author at first protects 5-position hydroxyl, then eliminates the 5-deoxidation quinic acid derivative be protected by reduction, and then by ion exchange resin go protection promptly obtain key intermediate (1R, 3R, 4S)-1,3,4-trihydroxy-methyl cyclohexanecarboxylaand.Finally obtain the homocitric acid lactone and the homocitric acid trimethyl of dimethyl protection again through reactions such as peroxidation, esterifications.The overall yield of reaction is 26.4%.Should be noted that the homocitric acid product of protection form need go protection just can obtain the homocitric acid lactone.This synthetic route complex operation, practicality is not high.
The Tatsumi group of Japan in 2005 (Tetrahedron Lett.2005,46,3815-3818) on the basis of Palmer group work, improve.Adopt 3-iodo propionic ester to substitute allyl bromide 98 as electrophilic reagent; by changing reaction conditions, improve temperature of reaction and prolonging (5 ℃ of reaction times; 10h) the be protected homocitric acid of form then obtains (R)-Gao lemon lactone, total recovery 32% in the acidic conditions protection of going down.This synthetic route has certain practical value, but is not suitable for macro preparation.
Summary of the invention
The objective of the invention is to the shortcoming that exists in the existing preparation homocitric acid lactone method, providing a kind of is raw material with 2-oxopentanedioic acid ester cheap, that be easy to get, can compactly, mass-producing prepare the method for racemic homocitric acid lactone.
Concrete synthetic route of the present invention is as follows:
The present invention includes following steps:
Step 1, compound 1 react 1～5h in the negative ion of a kind of ester and the formation of a kind of alkali in solvent, through extraction, concentrated, column chromatography purification, obtain compound 2, and the solvent that refers to here mainly is meant methylene dichloride or tetrahydrofuran (THF); Alkali is the hexamethyldisilazane lithium (LHMDS) of n-Butyl Lithium (n-BuLi) and hexamethyldisilazane (HMDS) formation or the diisopropylamine lithium (LDA) of n-Butyl Lithium and Diisopropylamine formation; Ester is ethyl acetate, methyl acetate or tert.-butyl acetate.
Step 2, compound 2 16h at least that refluxes in a kind of acid obtains homocitric acid lactone 3.Here the acid that refers to mainly is meant at least a in formic acid, acetate and the trifluoroacetic acid.
In step 1, the mol ratio of described alkali and ester is preferably 1: 1～and 2.
In step 2, the mol ratio of compound 2 and acid is preferably 1: 5～and 10.
The present invention be a kind of be raw material with 2-oxopentanedioic acid ester cheap, that be easy to get, the novel method of having synthesized racemic homocitric acid lactone efficiently.Compare with the synthetic route of having reported, synthetic route of the present invention the shortest (two steps), preparation technology is the simplest, and it is higher that each goes on foot reaction yield, and agents useful for same is common agents, has good application prospects.
Embodiment
Following examples further elaborate to the present invention.
Embodiment 1
Synthetic homocitric acid triethyl 2a: under ice bath, (0.35ml adds n-BuLi (2.5M solution in n-hexane in THF 1.65mmol) (1ml) solution to HMDS, 1.42mmol, 0.57ml), behind the reaction 30min, be cooled to-78 ℃, (0.37ml 1.42mmol), reacts 30min to add ethyl acetate, add 1a (238mg, 1.18mmol) THF (3.5ml) solution, the reaction 3h, add saturated NH
4The Cl quencher, extracted with diethyl ether merges organic phase, saturated common salt washing, anhydrous sodium sulfate drying.Rapid column chromatography (ethyl acetate: sherwood oil=1: 6～1: 4) obtain compound 2a, productive rate 73% behind filtration, the concentrating under reduced pressure.IR(film)ν
max：3505，2982，2938，1736，1446，1373，1191cm
-1；
1HNMR(400MHz，CDCl
3)δ：2.68(d，J＝16.2Hz，1H)，2.94(d，J＝16.2Hz，1H)，1.31(t，J＝7.1Hz，3H)，1.25(t，J＝7.1Hz，3H)，1.25(t，J＝7.1Hz，3H)，3.77(s，1H-OH)，4.13(qq，overlapped，J＝7.1Hz，4H)，4.22～4.31(m，2H)，2.02～2.07(m，2H)，2.21～2.29(m，1H)，2.46～2.54(m，1H)ppm；
13CNMR(100MHz，CDCl
3)δ：174.6，172.9，170.5，74.2，62.2，60.9，60.6，43.5，33.9，28.3，14.1ppm；Ms(ESI)：m/z308(M+H
2O，100)。
Synthetic homocitric acid lactone 3:
(1.05g 3.62mmol), is dissolved in (5mL) backflow 48h in 85% formic acid with compound 2a.Decompression removes formic acid removal and gets solid crude product, and recrystallization obtains pure homocitric acid lactone 3, productive rate 82%.IR(KBr)ν
max：1787，1730，1703cm
-1；
1H-NMR(DMSO-d6，500MHz)δ：3.08(d，J＝17.0Hz，1H)，2.85(d，J＝17.0Hz，1H)，2.66-2.54(m，2H)，2.38-2.24(m，2H)；
13C-NMR(DMSO-d6，125MHz)δ：176.55，172.46，170.64，82.87，41.41，30.98，27.65；HRMS?calcd?for[C
7H
8O
6-1]
-：187.0240，found：187.0237。
Embodiment 2
Method according to embodiment 1 prepares compound 2a by compound 1a.
Method according to embodiment 1 prepares compound 3 by compound 2a, replaces formic acid with trifluoroacetic acid, and all the other operations are identical, productive rate 91%.
Embodiment 3
Method according to embodiment 1 prepares compound 2a by compound 1a, and the mol ratio of alkali and ester is 1: 2.
Method according to embodiment 1 prepares compound 3 by compound 2a, adds trifluoroacetic acid in formic acid, and the proportioning of formic acid and trifluoroacetic acid is 1: 1, and the mol ratio of compound 2a and acid is 1: 10, and all the other operations are identical.
Embodiment 4
Similar to Example 1, its difference is that used ester adopts tert.-butyl acetate.
Embodiment 5
Similar to Example 1, its difference is used acid employing acetate.
Embodiment 6
Synthetic homocitric acid triethyl 2a: under ice bath, (0.28ml adds n-BuLi (2.5M solution in n-hexane in THF 2.00mmol) (1.3ml) solution to Diisopropylamine, 1.93mmol, 0.28ml), behind the reaction 30min, be cooled to-78 ℃, (0.48ml 1.84mmol), reacts 30min to add ethyl acetate, add 1a (186mg, 0.92mmol) THF (2.6ml) solution, the reaction 1h, add saturated NH
4The Cl quencher, extracted with diethyl ether merges organic phase, saturated common salt washing, anhydrous sodium sulfate drying.Rapid column chromatography (ethyl acetate: sherwood oil=1: 6～1: 4) obtain compound 2a, productive rate 65% behind filtration, the concentrating under reduced pressure.IR(film)ν
max：3505，2982，2938，1736，1446，1373，1191cm
-1；
1HNMR(400MHz，CDCl
3)δ：2.68(d，J＝16.2Hz，1H)，2.94(d，J＝16.2Hz，1H)，1.31(t，J＝7.1Hz，3H)，1.25(t，J＝7.1Hz，3H)，1.25(t，J＝7.1Hz，3H)，3.77(s，1H-OH)，4.13(qq，overlapped，J＝7.1Hz，4H)，4.22～4.31(m，2H)，2.02～2.07(m，2H)，2.21～2.29(m，1H)，2.46～2.54(m，1H)ppm；
13CNMR(100MHz，CDCl
3)δ：174.6，172.9，170.5，74.2，62.2，60.9，60.6，43.5，33.9，28.3，14.1ppm；Ms(ESI)：m/z308(M+H
2O，100)。
Prepare the method for compound 3 according to embodiment 1 by compound 2a, replace formic acid with trifluoroacetic acid, all the other operations are identical, productive rate 91%.
Embodiment 7
Method according to embodiment 6 prepares compound 2a by compound 1a, and the mol ratio of alkali and ester is 1: 1.5.
Method according to embodiment 6 prepares compound 3 by compound 2a, and the acid of being adopted is acetate and trifluoroacetic acid, and the proportioning of acetate and trifluoroacetic acid is 1: 1, and the mol ratio of compound 2a and acid is 1: 5, and all the other operations are identical.
Embodiment 8
Synthetic homocitric acid trimethyl 2b: under the ice bath, (1.04ml adds n-BuLi (2.5M solution in n-hexane in THF 4.9mmol) (3ml) solution to HMDS, 3.62mmol, 1.45ml), behind the reaction 30min, be cooled to-78 ℃, (0.3ml 3.62mmol), reacts 30min to add methyl acetate, add 1b (371mg, 2.13mmol) THF (4ml) solution, the reaction 5h, add saturated NH
4The Cl quencher, extracted with diethyl ether merges organic phase, saturated common salt washing, anhydrous sodium sulfate drying.Rapid column chromatography (ethyl acetate: sherwood oil=1: 6～1: 4) obtain compound 2b, productive rate 70% behind filtration, the concentrating under reduced pressure.IR(CH
2Cl
2)ν
max：3500，2956，1739，1439，1205cm
-1；
1H-NMR(CDCl
3，500MHz)δ：3.80(s，3H)，3.68-3.65(superposed，6H)，2.95(d，J＝16.0Hz，1H)，2.71(d，J＝16.0Hz，1H)，2.54-2.46(m，1H)，2.31-2.21(m，1H)，2.11-1.99(m，2H)；
13C-NMR(CDCl
3，125MHz)δ：174.59，172.90，170.59，73.91，52.58，51.47，51.31，42.88，33.51，27.70；MS(ESI，m/z)：249(M+H
+)，271(M+Na
+)。
Synthetic homocitric acid lactone 3: (0.98g 3.95mmol), is dissolved in (5mL) backflow 48h in 85% trifluoroacetic acid with compound 2b.Decompression is removed trifluoroacetic acid and is got solid crude product, and recrystallization obtains pure homocitric acid lactone 6, productive rate 91%.IR(KBr)ν
max：1787，1730，1703cm-1；1H-NMR(DMSO-d6，500MHz)δ：3.08(d，J＝17.0Hz，1H)，2.85(d，J＝17.0Hz，1H)，2.66-2.54(m，2H)，2.38-2.24(m，2H)；13C-NMR(DMSO-d6，125MHz)δ：176.55，172.46，170.64，82.87，41.41，30.98，27.65；HRMS?calcd?for[C7H806-1]-：187.0240，found：187.0237。
Embodiment 9
Similar to Example 8, its difference is the 16h at least that refluxes in trifluoroacetic acid.
Embodiment 10
Similar to Example 1, its difference is that used solvent is a methylene dichloride.
Claims (10)
1. preparation method of racemic homocitric acid lactone is characterized in that its synthetic route is as follows:
2. preparation method of racemic homocitric acid lactone as claimed in claim 1 is characterized in that its concrete steps are:
1) compound 1 reacts in the negative ion of a kind of ester and the formation of a kind of alkali in solvent, through extraction, concentrated, column chromatography purification, obtains compound 2;
2) compound 2 refluxes in a kind of acid, obtains homocitric acid lactone 3.
3. preparation method of racemic homocitric acid lactone as claimed in claim 2 is characterized in that compound 1 reacts 1～5h in solvent in the negative ion of a kind of ester and the formation of a kind of alkali.
4. as claim 2 or 3 described preparation method of racemic homocitric acid lactone, it is characterized in that described solvent is methylene dichloride or tetrahydrofuran (THF).
5. preparation method of racemic homocitric acid lactone as claimed in claim 2 is characterized in that described alkali is the hexamethyldisilazane lithium that n-Butyl Lithium and hexamethyldisilazane form, or the diisopropylamine lithium of n-Butyl Lithium and Diisopropylamine formation.
6. preparation method of racemic homocitric acid lactone as claimed in claim 2 is characterized in that described ester is ethyl acetate, methyl acetate or tert.-butyl acetate.
7. preparation method of racemic homocitric acid lactone as claimed in claim 2, the mol ratio that it is characterized in that described alkali and ester is 1: 1～2.
8. preparation method of racemic homocitric acid lactone as claimed in claim 2 is characterized in that described backflow 16h at least.
9. preparation method of racemic homocitric acid lactone as claimed in claim 2 is characterized in that described acid is at least a in formic acid, acetate and the trifluoroacetic acid.
10. preparation method of racemic homocitric acid lactone as claimed in claim 2 is characterized in that the mol ratio of described compound 2 and acid is 1: 5～10.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103880789A (en) * | 2014-02-19 | 2014-06-25 | 成都中医药大学 | Furan lactone ring derivative and application thereof |
| US8940920B2 (en) | 2013-06-21 | 2015-01-27 | Tallinn University Of Technology | Method for preparation of (2-hydroxy-3-oxo-cyclopent-1-enyl)-acetic acid esters |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005075734A (en) * | 2003-08-28 | 2005-03-24 | Japan Science & Technology Agency | Method for producing optically active homocitric acid |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8940920B2 (en) | 2013-06-21 | 2015-01-27 | Tallinn University Of Technology | Method for preparation of (2-hydroxy-3-oxo-cyclopent-1-enyl)-acetic acid esters |
| CN103880789A (en) * | 2014-02-19 | 2014-06-25 | 成都中医药大学 | Furan lactone ring derivative and application thereof |
| CN103880789B (en) * | 2014-02-19 | 2016-02-03 | 成都中医药大学 | Furans lactonic ring analog derivative and uses thereof |
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