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
- Publication number
- 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
- Authority
- CN
- China
- Prior art keywords
- methyl
- dihydro
- add
- benzyl
- oxazines
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- OSCCDBFHNMXNME-YUPRTTJUSA-N (4S)-4-hydroxy-L-isoleucine zwitterion Chemical compound C[C@H](O)[C@H](C)[C@H](N)C(O)=O OSCCDBFHNMXNME-YUPRTTJUSA-N 0.000 title claims abstract description 23
- OSCCDBFHNMXNME-UHFFFAOYSA-N gamma-hydroxyisoleucine Natural products CC(O)C(C)C(N)C(O)=O OSCCDBFHNMXNME-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 238000010189 synthetic method Methods 0.000 title claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- QBCUUJGHWFKMDC-JTQLQIEISA-N (3s)-3-hydroxy-4-phenylbutan-2-one Chemical compound CC(=O)[C@@H](O)CC1=CC=CC=C1 QBCUUJGHWFKMDC-JTQLQIEISA-N 0.000 claims abstract description 14
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 22
- 239000012044 organic layer Substances 0.000 claims description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 229920006395 saturated elastomer Polymers 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 16
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 239000000706 filtrate Substances 0.000 claims description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 235000002639 sodium chloride Nutrition 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 7
- 239000011780 sodium chloride Substances 0.000 claims description 7
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 239000000284 extract Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- ONIKNECPXCLUHT-UHFFFAOYSA-N 2-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Cl ONIKNECPXCLUHT-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 235000019270 ammonium chloride Nutrition 0.000 claims description 4
- 239000012141 concentrate Substances 0.000 claims description 4
- 230000006837 decompression Effects 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 4
- 239000011261 inert gas Substances 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- 239000000376 reactant Substances 0.000 claims description 4
- 239000011592 zinc chloride Substances 0.000 claims description 4
- QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical group CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 claims description 3
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 235000019441 ethanol Nutrition 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- -1 filtering Substances 0.000 claims description 3
- 239000007789 gas Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- 238000010792 warming Methods 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 208000021302 gastroesophageal reflux disease Diseases 0.000 claims description 2
- 238000013517 stratification Methods 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims 2
- 238000002360 preparation method Methods 0.000 abstract description 7
- 230000000977 initiatory effect Effects 0.000 abstract description 5
- 239000000463 material Substances 0.000 abstract description 5
- 238000011084 recovery Methods 0.000 abstract description 5
- 238000005516 engineering process Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 230000008878 coupling Effects 0.000 abstract description 2
- 238000010168 coupling process Methods 0.000 abstract description 2
- 238000005859 coupling reaction Methods 0.000 abstract description 2
- 230000007062 hydrolysis Effects 0.000 abstract description 2
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 2
- 238000007363 ring formation reaction Methods 0.000 abstract description 2
- RWMGQGIAEZVPKY-UHFFFAOYSA-N 1-hydroxy-4-phenylbutan-2-one Chemical compound OCC(=O)CCC1=CC=CC=C1 RWMGQGIAEZVPKY-UHFFFAOYSA-N 0.000 abstract 1
- 238000000034 method Methods 0.000 description 9
- 206010012601 diabetes mellitus Diseases 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 206010022489 Insulin Resistance Diseases 0.000 description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 4
- 244000250129 Trigonella foenum graecum Species 0.000 description 3
- 235000001484 Trigonella foenum graecum Nutrition 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 235000001019 trigonella foenum-graecum Nutrition 0.000 description 3
- 0 *C([C@](Cc1ccccc1)N)O Chemical compound *C([C@](Cc1ccccc1)N)O 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 230000003914 insulin secretion Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 1
- 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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 150000008547 L-phenylalanines Chemical class 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 241001312519 Trigonella Species 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- MQRJBSHKWOFOGF-UHFFFAOYSA-L disodium;carbonate;hydrate Chemical class O.[Na+].[Na+].[O-]C([O-])=O MQRJBSHKWOFOGF-UHFFFAOYSA-L 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 239000001917 trigonella foenum graecum l. absolute Substances 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510067089.8A CN104649918B (en) | 2015-02-09 | 2015-02-09 | A kind of synthetic method of (2S, 3R, 4S)-4-hydroxyisoleucine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510067089.8A CN104649918B (en) | 2015-02-09 | 2015-02-09 | A kind of synthetic method of (2S, 3R, 4S)-4-hydroxyisoleucine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104649918A CN104649918A (en) | 2015-05-27 |
| CN104649918B true CN104649918B (en) | 2016-09-07 |
Family
ID=53241624
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510067089.8A Expired - Fee Related CN104649918B (en) | 2015-02-09 | 2015-02-09 | A kind of synthetic method of (2S, 3R, 4S)-4-hydroxyisoleucine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104649918B (en) |
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 | 4-Hydroxyisoleucine analogs and uses thereof |
-
2015
- 2015-02-09 CN CN201510067089.8A patent/CN104649918B/en not_active Expired - Fee Related
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 | 4-Hydroxyisoleucine analogs 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 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104649918A (en) | 2015-05-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106349245A (en) | Sitagliptin phosphate impurities, method for preparing same and application of sitagliptin phosphate impurities | |
| CN105348154B (en) | The recovery method of sulfosalicylic acid in a kind of Doxycycline production waste liquid | |
| CN102050781A (en) | Industrial preparation method of hydroxychloroquine sulfate | |
| CN105017082A (en) | Preparation method of cardiotonic drug Entresto key intermediate (R)-tert-butyl-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate | |
| CN104356016B (en) | A method of with recycling preparation 3- isobutylglutaric acid monoamides | |
| CN104649300A (en) | Method for recovering and refining sodium bromide from dipropyl cyanoacetate mixture | |
| CN104649918B (en) | A kind of synthetic method of (2S, 3R, 4S)-4-hydroxyisoleucine | |
| CN102775443B (en) | The synthetic method of Chlorpyrifos 94 | |
| CN103804267A (en) | Simple environment-friendly synthesis process of vildagliptin | |
| CN102241599B (en) | Method for preparing glycine | |
| CN102408329B (en) | 2, the preparation method of 4-dihydroxybenzoic acid | |
| CN105348323A (en) | Chlorpyrifos aqueous-phase synthesizing method with trichloro-acetic chloride as primary raw material | |
| CN105859608B (en) | A method of preparing half tartrate crystal form B of piperazine Ma Selin | |
| CN106316956A (en) | Industrial production method for pyrazole | |
| CN104817482B (en) | 2-substituted pyrrolidine compound, preparation method and application thereof in preparation of vildagliptin | |
| CN1321122C (en) | A method for hydrothermally synthesizing gadolinium-diethylenetriaminepentaacetic acid | |
| CN100395230C (en) | Method for preparing high-purity gahapentin | |
| CN1257163C (en) | Method for synthesizing 1-acetyl-4-(4-hydroxy pheny) piperazine | |
| CN102503853A (en) | Synthesis method of benzophenone hydrazone | |
| CN106380377A (en) | Preparation method of syn-p-menthyl-3,8-diol | |
| CN101402576A (en) | Method for producing bi(2-hydroxyethyl)imino-tri(hydroxymethyl)methyl hydride | |
| CN102875460A (en) | Method for preparing sorafenib | |
| CN101054366B (en) | Method of synthesizing 1-methyl hydantoin | |
| CN103992241A (en) | Preparation method of N-substituted phenyl glycine | |
| CN107686439A (en) | A kind of preparation method of the key intermediate of ALK inhibitor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160907 Termination date: 20200209 |