CN104649918B - A kind of synthetic method of (2S, 3R, 4S)-4-hydroxyisoleucine - Google Patents
A kind of synthetic method of (2S, 3R, 4S)-4-hydroxyisoleucine Download PDFInfo
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- CN104649918B CN104649918B CN201510067089.8A CN201510067089A CN104649918B CN 104649918 B CN104649918 B CN 104649918B CN 201510067089 A CN201510067089 A CN 201510067089A CN 104649918 B CN104649918 B CN 104649918B
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- 0 *C([C@](Cc1ccccc1)N)O Chemical compound *C([C@](Cc1ccccc1)N)O 0.000 description 2
- YEHRTTZJTORGJL-VIFPVBQESA-N C[C@@H](Cc1ccccc1)C(C)=O Chemical compound C[C@@H](Cc1ccccc1)C(C)=O YEHRTTZJTORGJL-VIFPVBQESA-N 0.000 description 1
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Abstract
The invention discloses the synthetic method of one (2S, 3R, 4S) 4 hydroxyisoleucine, with (S) 3 hydroxyl 4 phenyl 2 butanone as raw material, through cyclization, coupling, hydrogenate, reduce and hydrolyze and prepare (2S, 3R, 4S) 4 hydroxyisoleucine.Its preparation technology synthetic route is short, and reaction condition is gentle, simple to operate, safety, and total recovery is high, is suitable for industrialization and amplifies.And initiation material (S) 3 hydroxyl 4 phenyl 2 butanone can recycle: generate target product (2S in final step hydrolysis, 3R, 4S) during 4 hydroxyisoleucine, initiation material (S) 3 hydroxyl 4 phenyl 2 butanone generates simultaneously and reclaims, and the rate of recovery reaches more than 62%；(S) 3 hydroxyl 4 phenyl 2 butanone reclaimed can recycle again.
Description
Technical field
The invention belongs to organic chemistry and medicinal chemistry art, be specifically related to the synthesis side of one (2S, 3R, 4S)-4-hydroxyisoleucine
Method.
Background technology
At present, diabetes have become as a worldwide problem, and 90% in total diabetes is diabetes B, it has also become each
The major public health problem that state pays close attention to.Pulse family Trigonella plant fenugreek (Trigonellafoenum graecum) has hypoglycemic
Act on improving insulin resistance (insulinresistance) etc..Research shows, insulin resistance is metabolic syndrome and 2 types
Common pathologic, physiologic phenomenon in the pathogenesis such as diabetes.Therefore, the key that insulin resistance is preventing and treating diabetes B is improved.
4-hydroxyisoleucine is a kind of sequestered amino acid being separated to from fenugreek, can strengthen the acceptor sensitivity to insulin
Property, there is stronger insulin secretion accelerating activity.Research display, in its up to 8 kinds stereoisomers, (2S, 3R, 4S)-4-
Hydroxyisoleucine insulin secretion accelerating activity is the strongest, can be used for treating diabetes B.
At present, the main source of (2S, 3R, 4S)-4-hydroxyisoleucine is fenugreek seed.But from natural plants, extract separation be subject to
To resource constraint, limits throughput, Simultaneous purification difficulty is big, it is difficult to prepare high sterling in a large number.(2S, 3R, 4S)-4-hydroxyisoleucine
Prof. Du Yucang appear in the newspapers, but most of document report synthetic route tediously long, total recovery is low, raw materials used costliness.Shimizu
(Biosci.Biotechnol.Biochem., 2007,71,1607-1615.), Kivero (Applied Biochemistry and
Microbiology, 2012,48,639-644.) report respectively with Smirnov (Microbiol.Lett., 2012,331,97-104.)
A kind of method by Enzyme catalyzed synthesis 4-hydroxyisoleucine.But the acquisition of biology enzyme used by these methods is difficult, reaction effect
Rate is the highest, and product stereoselectivity is the most unsatisfactory.Sasaki (Eur.J.org.Chem., 2002,834-839.) is in 2002
Year reported first is a kind of by the method for organic fully synthetic preparation (2S, 3R, 4S)-4-hydroxyisoleucine.But because of synthesis technique step
Long, operation complexity, be not suitable for industrialized production.Kumaraswamy (J.Org.Chem.2010,75,2745-2747.) in 2010
Report a kind of method by chiral organicatalyst synthesis (2S, 3R, 4S)-4-hydroxyisoleucine.But this synthesis technique is because using
Ozone, dangerous height, and the chiral organicatalyst used synthesize the reasons such as more difficult, expensive, are difficult to equally industrialize.
In order to enable to produce high-purity (2S, 3R, 4S)-4-hydroxyisoleucine in a large number, it is necessary to research one can be suitable for industrial new conjunction
One-tenth method.
Summary of the invention
Present invention aim at providing the synthetic method of a kind of (2S, 3R, 4S)-4-hydroxyisoleucine being applicable to industrialized production.
For reaching above-mentioned purpose, use technical scheme as follows:
A kind of synthetic method of (2S, 3R, 4S)-4-hydroxyisoleucine, with (S)-3-hydroxy-4-phenyl-2-butanone as raw material, through cyclization,
Coupling, hydrogenate, reduce and hydrolyze and prepare (2S, 3R, 4S)-4-hydroxyisoleucine.
By such scheme, the synthetic method of described (2S, 3R, 4S)-4-hydroxyisoleucine, comprise the following steps:
1) by (S)-3-hydroxy-4-phenyl-2-butanone, the acid of N-Boc-ethamine, DIPEA mixing in dichloromethane,
It is cooled to 0-5 DEG C of dropping chlorobenzoyl chloride, insulated and stirred 5-7h；Water destruct is added, organic layer saturated sodium carbonate water after reaction completely
Solution washs；Add stratification after mixed in hydrochloric acid stirring 1h, organic layer is concentrated and dried；Add ethyl acetate, and use carbon
Adding anhydrous sodium sulfate after acid sodium regulation pH value neutrality to be dried, filter, filtrate obtains (S)-6-benzyl-5-methyl after being concentrated to dryness
-3,6-dihydro-2H-1,4-oxazines-2-ketone；
2) anhydrous THF and (S)-6-benzyl-5-methyl-3,6-dihydro-2H-1,4-oxazines-2-ketone mixes, is cooled to 0-5 Celsius
Spend and be incubated, adding anhydrous zinc dichloride stirring mixing 10min, dropping potassium tert-butoxide stirring mixing 1h, add diacetyl stirring
Mixing 3h, then warms naturally to room temperature, adds saturated aqueous ammonium chloride and destroys；Reactant liquor methyl tertiary butyl ether(MTBE) extracts,
Organic layer saturated aqueous common salt washs, and is dried, filters and concentrates, and ethyl acetate-petroleum ether crystallization obtains (S, E)-6-benzyl-5-methyl
-3-(3-oxo butyl-2-subunit)-3,6-dihydro-2H-1,4-oxazines-2-ketone；
3) ethyl acetate and S, E)-6-benzyl-5-methyl-3-(3-oxo butyl-2-subunit)-3,6-dihydro-2H-1,4-oxazines-2-ketone mix
Close, under inert gas shielding, add 5%Pd/C, be passed through hydrogen reaction 10h, empty and be passed through inert gas, filter, concentrate,
It is dried to obtain (3S, 6S)-6-benzyl-5-methyl-3-((R)-3-oxo butyl-2-yl)-3,6-dihydro-2H-1,4-oxazines-2-ketone；
4) isopropanol, (3S, 6S)-6-benzyl-5-methyl-3-((R)-3-oxo butyl-2-yl)-3,6-dihydro-2H-1,4-are disliked
Piperazine-2-ketone, aluminium isopropoxide mix and are warming up to 60-65 DEG C, are concentrated to dryness after reaction completely；Add hydrochloric acid reflux, be cooled to room
Methyl tertiary butyl ether(MTBE) extraction after temperature；Organic layer saturated aqueous common salt washs, and is dried, filters, is concentrated to dryness；133-135 is collected in rectifying
DEG C cut, reclaims starting material (S)-3-hydroxy-4-phenyl-2-butanone；Being washed by organic layer after extraction, be dried and reduce pressure, it is molten to boil off
Agent, adds methyl tertiary butyl ether(MTBE) and is passed through hydrogen chloride gas tune pH to 2.5；Decompression boils off solvent, obtains white with ethyl alcohol recrystallization
Look acicular crystal thing (2S, 3R, 4S)-4-hydroxyisoleucine.
Synthetic route of the present invention is as follows:
Wherein, a represents 1) acid of N-Boc-ethamine, DIPEA, chlorobenzoyl chloride；2) hydrochloric acid；B represents fourth two
Ketone, ZnCl2, potassium tert-butoxide；C represents 5%Pd/C, H2；D represents 1) Al (OiPr)3；2) hydrochloric acid.
The present invention has the beneficial effect that:
The preparation technology synthetic route of the present invention is short, and reaction condition is gentle, simple to operate, safety, and total recovery is high, is suitable for industry
Change and amplify.And initiation material (S)-3-hydroxy-4-phenyl-2-butanone can recycle: generate target in final step hydrolysis and produce
During thing (2S, 3R, 4S)-4-hydroxyisoleucine, initiation material (S)-3-hydroxy-4-phenyl-2-butanone generates simultaneously and reclaims, the rate of recovery
Reach more than 62%.(the S)-3-hydroxy-4-phenyl-2-butanone reclaimed can recycle again.
Detailed description of the invention
Following example explain technical scheme further, but not as limiting the scope of the invention.
The building-up process of initiation material (S)-3-hydroxy-4-phenyl-2-butanone is as follows:
In reaction bulb, add 400mL 1N sulfuric acid and 34 grams of L-phenylalanines, stirring, after being cooled to 0-5 degree, add Asia
Sodium nitrate solution (28 grams of natrium nitrosums are dissolved in 25mL water).Stir 2 hours at 0-5 degree, be warmed to room temperature reaction 10 hours,
Add the extraction of 500mL methyl tertiary butyl ether(MTBE) after reaction completely, after organic layer saturated aqueous sodium carbonate is adjusted to neutrality, use salt
Water washs.Organic layer anhydrous sodium sulfate is dried, and filters, and filtrate is concentrated to dryness.Product is proceeded to reaction bulb, add 200mL without
Water THF, after being cooled to 0-5 degree, after slowly dripping lithium methide (0.45mol), after being warmed to room temperature reaction 5 hours, slowly
Add saturated aqueous ammonium chloride cancellation reaction.Reactant liquor adds methyl tertiary butyl ether(MTBE) extraction, and organic layer uses saturated sodium carbonate successively
After the aqueous solution and saturated aqueous common salt washing, add anhydrous sodium sulfate and be dried.Filtering, filtrate is concentrated to dryness, and 133-135 is collected in rectifying
Degree cut (vacuum: 10mmHg) obtains (S)-3-hydroxy-4-phenyl-2-butanone 30 grams.
Embodiment
(S) preparation of-6-benzyl-5-methyl-3,6-dihydro-2H-1,4-oxazines-2-ketone
In reaction bulb, add 200mL and be dried 1 dichloromethane, 16 grams of (S)-3-hydroxy-4-phenyl-2-butanone, 18 grams of N-BOC-
Aminoacetic acid, 16 grams of DIPEAs (DIPEA).It is cooled to 0-5 degree 15 grams of chlorobenzoyl chlorides of dropping, after dropping
0-5 degree stirs 6 hours.Adding water destruct after reaction completely, organic layer saturated aqueous sodium carbonate washs.Organic layer adds 100mL
1N HCl, after stirring 1 hour, layering, after organic layer is concentrated to dryness, add 200mL ethyl acetate, in modulating with sodium carbonate
After property, adding anhydrous sodium sulfate and be dried, filter, filtrate is concentrated to dryness (S)-6-benzyl-5-methyl-3,6-dihydro-2H-1,4-oxazines
-2-ketone 16 grams.
The preparation of (S, E)-6-benzyl-5-methyl-3-(3-oxo butyl-2-subunit)-3,6-dihydro-2H-1,4-oxazines-2-ketone
In reaction bulb, the addition anhydrous THF of 150mL, 16 grams of (S)-6-benzyl-5-methyl-3,6-dihydro-2H-1,4-oxazines-2-ketone,
After being cooled to 0-5 degree, add 16 grams of anhydrous zinc dichloride, after stirring 10 minutes, be slowly added into 11 grams of potassium tert-butoxides.Stirring
After 1 hour, add diacetyl 12 grams.After 0-5 degree stirs 3 hours, slowly it is warmed to room temperature stirring 1 hour.Reaction is completely
After add saturated aqueous ammonium chloride destroy.Reactant liquor methyl tertiary butyl ether(MTBE) extracts, and organic layer saturated aqueous common salt washs, organic
Layer anhydrous sodium sulfate is dried, and filters, and filtrate is concentrated to dryness.Crude product ethyl acetate-petroleum ether crystallization obtains product (S, E)-6-benzyl
-5-methyl-3-(3-oxo butyl-2-subunit)-3,6-dihydro-2H-1,4-oxazines-2-ketone 19 grams.
The preparation of (3S, 6S)-6-benzyl-5-methyl-3-((R)-3-oxo butyl-2-yl)-3,6-dihydro-2H-1,4-oxazines-2-ketone
In reaction bulb, add 200mL ethyl acetate, 19 grams of (S, E)-6-benzyl-5-methyl-3-(3-oxo butyl-2-subunit)-3,6-
Dihydro-2H-1,4-oxazines-2-ketone, reaction bulb vacuumizes, and nitrogen is replaced 2 times, keeps nitrogen atmosphere, is subsequently adding 2 grams of 5%Pd/C.
Reaction bulb vacuumizes, hydrogen exchange 2 times, starts to be hydrogenated with (1atm).After reaction 10h, reaction completely, empties hydrogen, nitrogen
Displacement once, is filtered, and filtrate is concentrated to dryness (3S, 6S)-6-benzyl-5-methyl-3-((R)-3-oxo butyl-2-yl)-3,6-dihydro
-2H-1,4-oxazines-2-ketone 19 grams.
The preparation of (2S, 3R, 4S)-4-hydroxyisoleucine
In reaction bulb, add 200mL dry isopropyl, 19 grams of (3S, 6S)-6-benzyl-5-methyl-3-((R)-3-oxo butyl-2-
Base)-3,6-dihydro-2H-1,4-oxazines-2-ketone, 4 grams of aluminium isopropoxides, it is warming up to the reaction of 60-65 degree, after reaction completely, reduces pressure dense
It is reduced to do.Add 300mL 1N hydrochloric acid, reflux 6 hours, after being cooled to room temperature, extract with methyl tertiary butyl ether(MTBE).Organic layer
After washing with saturated aqueous common salt, adding anhydrous sodium sulfate and be dried, filter, filtrate is concentrated to dryness, and 133-135 degree cut is collected in rectifying
(vacuum: 10mmHg) reclaims starting material (S)-3-hydroxy-4-phenyl-2-butanone 10 grams.Water layer 30% sodium hydrate aqueous solution
After regulation PH to 3-4, then regulate PH to 9-10 with saturated aqueous sodium carbonate.Extracting with dichloromethane, organic layer is with saturated
Salt solution washs, and anhydrous sodium sulfate filters after drying, and filtrate decompression boils off solvent.Add 90mL methyl tertiary butyl ether(MTBE), slowly lead to
Enter hydrogen chloride gas, adjust pH to 2.5.Decompression boils off solvent, with ethyl alcohol recrystallization 2 times, obtains white, needle-shaped crystals 8 grams, mp
223-226 DEG C, [a]D 20+ 32.5 (C=1.0, H2O)。
Claims (1)
1. the synthetic method of (2S, 3R, 4S)-4-hydroxyisoleucine, it is characterised in that comprise the following steps:
1) by (S)-3-hydroxy-4-phenyl-2-butanone, the acid of N-Boc-ethamine, DIPEA mixing in dichloromethane, it is cooled to 0-5 DEG C of dropping chlorobenzoyl chloride, insulated and stirred 5-7h；Adding water destruct after reaction completely, organic layer saturated aqueous sodium carbonate washs；Add stratification after mixed in hydrochloric acid stirring 1h, organic layer is concentrated and dried；Adding ethyl acetate, and be dried with adding anhydrous sodium sulfate after sodium carbonate regulation pH value neutrality, filter, filtrate obtains (S)-6-benzyl-5-methyl-3,6-dihydro-2H-1,4-oxazines-2-ketone after being concentrated to dryness；
2) anhydrous THF and (S)-6-benzyl-5-methyl-3,6-dihydro-2H-1,4-oxazines-2-ketone mixes, it is cooled to 0-5 degree Celsius and is incubated, add anhydrous zinc dichloride stirring mixing 10min, dropping potassium tert-butoxide stirring mixing 1h, add diacetyl stirring mixing 3h, then warm naturally to room temperature, add saturated aqueous ammonium chloride and destroy；Reactant liquor methyl tertiary butyl ether(MTBE) extracts, and organic layer saturated aqueous common salt washs, and is dried, filters and concentrates, ethyl acetate-petroleum ether crystallization obtains (S, E)-6-benzyl-5-methyl-3-(3-oxo butyl-2-subunit)-3,6-dihydro-2H-1,4-oxazines-2-ketone；
3) ethyl acetate and (S; E)-6-benzyl-5-methyl-3-(3-oxo butyl-2-subunit)-3; 6-dihydro-2H-1,4-oxazines-2-ketone mixes, and adds 5%Pd/C under inert gas shielding; it is passed through hydrogen reaction 10h; empty and be passed through inert gas, filtering, concentrate, be dried to obtain (3S, 6S)-6-benzyl-5-methyl-3-((R)-3-oxo butyl-2-yl)-3; 6-dihydro-2H-1,4-oxazines-2-ketone；
4) by isopropanol, (3S, 6S)-6-benzyl-5-methyl-3-((R)-3-oxo butyl-2-yl)-3,6-dihydro-2H-1,4-oxazines-2-ketone, aluminium isopropoxide mix and are warming up to 60-65 DEG C, are concentrated to dryness after reaction completely；Add hydrochloric acid reflux, be cooled to methyl tertiary butyl ether(MTBE) extraction after room temperature；Organic layer saturated aqueous common salt washs, and is dried, filters, is concentrated to dryness；133-135 DEG C of cut is collected in rectifying, reclaims starting material (S)-3-hydroxy-4-phenyl-2-butanone；After extraction, organic layer washed, be dried and reduce pressure and boil off solvent, add methyl tertiary butyl ether(MTBE) and be passed through hydrogen chloride gas tune pH to 2.5；Decompression boils off solvent, obtains white, needle-shaped crystals thing (2S, 3R, 4S)-4-hydroxyisoleucine with ethyl alcohol recrystallization.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1784378A (en) * | 2003-05-07 | 2006-06-07 | 国家科研中心 | Method for the synthesis of 4-hydroxyisoleucine and the derivatives thereof |
| CN101193852A (en) * | 2005-02-18 | 2008-06-04 | 因诺迪亚有限公司 | Analogs of 4-hydroxyisoleucine and uses thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1784378A (en) * | 2003-05-07 | 2006-06-07 | 国家科研中心 | Method for the synthesis of 4-hydroxyisoleucine and the derivatives thereof |
| CN101193852A (en) * | 2005-02-18 | 2008-06-04 | 因诺迪亚有限公司 | Analogs of 4-hydroxyisoleucine and uses thereof |
Non-Patent Citations (1)
| Title |
|---|
| 4-羟基异亮氨酸的研究进展;刘玲 等;《天然产物研究与开发》;20061231;第18卷;491-496 * |
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