CN106632361B - A kind of method of synthesizing optical Pure biotin intermediate lactone - Google Patents
A kind of method of synthesizing optical Pure biotin intermediate lactone Download PDFInfo
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- CN106632361B CN106632361B CN201611072814.1A CN201611072814A CN106632361B CN 106632361 B CN106632361 B CN 106632361B CN 201611072814 A CN201611072814 A CN 201611072814A CN 106632361 B CN106632361 B CN 106632361B
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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Abstract
The present invention relates to a kind of methods that catalysis desymmetrization reduction acid anhydrides I prepares optical voidness Biotin intermediate lactone II.The method has catalyst amount low using biotin intermediate acid anhydrides I as reaction substrate, in the transition metal-catalyzed lower method for preparing optical voidness Biotin intermediate lactone II compared to conventional method, high conversion rate,eeValue is high, and cost is relatively low, and easy to operate, environmentally protective feature, is suitable for large-scale industrial production.
Description
Technical field
The invention belongs to organic chemistry fileds, and in particular to a kind of method of synthesizing optical Pure biotin intermediate lactone.
Background technology
(+)-biotin (Biotin) is also known as biotin, vitamin B7, is a kind of water-soluble B vitamin.It is a kind of
It maintains human body natural to grow, nutrient necessary to development and normal human's function, is widely used in medicine, feed, biotechnology
Etc. industries.
At present industrial production biotin be mostly based on improved Sternbach methods (refer to US2,489,235, US2,
489,238, US3,740,416, US4,014,895, US3,876,656, US4,403,096, JP61254590), the pass of the method
Key is synthesis optical voidness S intermediates (3aS, 6aR)-lactone as shown in Formula II, has numerous methods to describe the synthesis of the lactone.One
Kind is racemic naphthenic acid monocycle hexanol ester to be made in cyclic acid anhydride and cyclohexanol mono-esterification, then carry out diastereomeric with chiral selectors
Body crystallization splits into required (3aS, 6aR)-naphthenic acid monoesters, and then is obtained among crucial chirality through lithium borohydride reduction, cyclization
Body (3aS, 6aR)-lactone.Common chiral selectors have pseudoephedrine (Helv.Chim.Acta 1970,53,991-
999), dehydroabietylamine (EP173185A1), (S) -2- amino -1,1- diphenyl propyl alcohol (EP92194A1), (1S, 2S)-Soviet Union
Formula -1- (p-nitrophenyl) -1,3-PD etc..However, the side of above-mentioned acquisition key chiral intermediate (3aS, 6aR)-lactone
Method has cumbersome, single fractionation rate low (30% or so) and defect of high cost.Another kind of synthesis of chiral intermediate
The method of (3aS, 6aR)-lactone is to carry out cis-selectivity open loop in turn through a series of officials to cyclic acid anhydride using chiral auxiliary
Conversion can be rolled into a ball to obtain.If common chiral auxiliary is (S)-N- methyl-phenyl ethylamine (EP44158A1), N-methylephedrine
(WO2001025215A2), chiral alcohol (WO2004094367A2) etc..Often stereoselectivity and yield are all preferable for such method,
But disadvantage is that it is still necessary to cumbersome steps could obtain (3aS, 6aR)-lactone, and yield is not high, and chiral reagent price used is high
Expensive, recycling difficulty etc..The method that third class prepares chiral intermediate (3aS, 6aR)-lactone is catalyzed using enzyme or small molecule
Method obtains.Optically pure carboxylic acid intermediate such as is obtained using the method for pork liver enzymatic hydrolysis meso dimethyl ester, is then passed through
Serial functional group conversions obtain chiral (3aS, 6aR)-lactone (EP84892A2；Adv.Synth.Catal.2005,347,549-
554.).This method tends to obtain preferable optical selective, but due to enzyme is variable, content is low, extraction detaches difficulty etc.,
Industrial applications are restricted.It is that catalyst prepares chiral (3aS, 6aR)-lactone to cyclic acid anhydride open loop using organic molecule,
Common micromolecule catalyst is quinoline DHQD-PHN (Synthesis 2001,1737-1741), Chiral Amine (1S,
2R) -1- (4- nitrobenzophenones) -2-N, N- dimethylamino -3- trityloxy -1- propyl alcohol (Adv.Synth.Catal.2009,
351 (4), 547-552), cinchona alkaloids (CN101215291A, CN101284837A), BINOL
(Tetrahedron Lett.1993,34 (7), 1167-70) etc..Although this method yield and selectivity are preferably, catalyst preparation
It is cumbersome, and dosage is larger, practical value is restricted.The method that 4th class prepares chiral intermediate (3aS, 6aR)-lactone is
Utilize the method for chiral pond (Chiral Pool).As Seki successively report with L-Aspartic acid (Synthesis 2002,
361-364.) and L-cysteine (Chem.-Eur.J.2004,10 (23), 6102-6110) is chiral pond, synthesis of chiral
(3aS, 6aR)-lactone；Deshmukh et al. reacted through 7 steps using the chiral lactam that easily prepares as synthon prepare it is chiral (3aS,
6aR)-lactone (Synthesis 2007,1159-1164)；It is that chiral pond is closed that Chen Fener, which reported D-MANNOSE equal to 2007,
At chiral (3aS, 6aR)-lactone (Carbohydrate Res.2007,342,2461-2464).Above method step compared with
It is cumbersome, using being restricted.
In addition, also having the method for a kind of synthesis of chiral intermediate (3aS, 6aR)-lactone is handled using cyclic acid anhydride as raw material
Property catalyst desymmetrization reaction, a step efficiently synthesizes chiral (3aS, 6aR)-lactone.Such as utilization [Rh (NBD) Cl]2, it is chiral
Ferrocene ligands do catalyst, asymmetric reduction acid anhydrides, but yield and stereoselectivity it is bad (Tetrahedron 2011,67,
10006-10010)；2012 Nian Zhangxumu seminars utilize [Ir (cod) Cl]2, C3*-TunePhos do catalyst, catalytic hydrogenation
Acid anhydrides, realizes the asymmetric reduction of acid anhydrides with higher yield and ee values, and turn over number can reach 2000 (Org.Lett.2013,
15,1740-1743), the efficiency of this method cannot still meet industrial needs.Therefore, to optical voidness biotin intermediate
Suitable green chemistry process route is found in the improvement developmental research of lactone synthetic technology, is had important economic value and is showed
Real demand.
Invention content
The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide it is a kind of green, efficiently prepare light
The method for learning Pure biotin key intermediate (3aS, 6aR)-lactone.
The technical solution adopted by the present invention is：
Using biotin intermediate acid anhydrides is reaction substrate shown in formula (I), in organic solvent, it is added transition metal-catalyzed
Agent, occurs desymmetrization acid anhydrides reduction reaction 6-72 hours under 50-150bar atmosphere of hydrogen, under the conditions of 50-150 DEG C, so
After filter out catalyst, optical voidness biotin intermediate (3aS, 6aR)-lactone shown in formula (II) is obtained after recrystallization；
Wherein formula (I) (II) is as follows：
Organic solvent used is following one or more mixture：Dichloromethane, toluene, n-hexane, hexamethylene,
Ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran, 1,4- dioxane, ethyl acetate, isopropyl acetate, methyl formate, formic acid second
Ester, methanol, ethyl alcohol, isopropanol, trifluoroethanol, formic acid, acetic acid, acetonitrile.
Reaction substrate initial concentration is 1-700g/L in the organic solvent, and the addition of transition-metal catalyst is 20-
1000mg/L。
Preferably, the organic solvent is tetrahydrofuran, Isosorbide-5-Nitrae-dioxane or their mixture.
Preferably, a concentration of 200-400g/L of reaction substrate.
The reaction equation that above-mentioned reaction process is related to is as follows：
The preparation method of transition-metal catalyst is：Under nitrogen atmosphere, in organic solvent, transition metal is sequentially added
Precursor and chiral ligand stir 0.25-3 hours at 10-50 DEG C, and transition-metal catalyst is made.
During preparing transition-metal catalyst,
The organic solvent is dichloromethane, toluene, n-hexane, hexamethylene, ether, methyl tertiary butyl ether(MTBE), tetrahydrochysene furan
It mutters, 1,4- dioxane, ethyl acetate, isopropyl acetate, methyl formate, Ethyl formate, methanol, ethyl alcohol, isopropanol, trifluoro second
One or more of alcohol, formic acid, acetic acid, acetonitrile.
The transition metal precursors are [Ir (COD) Cl]2、[Ir(NBD)Cl]2、[Ir(CH2CH2)2Cl]2、[Ir
(COD)2]X、[Ir(NBD)2] X, wherein X is balance anion, selected from halogen, BF4、B(Ar)4、ClO4、SbF6、PF6Or
CF3SO3。
The chiral ligand is following one or more mixture：TangPhos,DuanPhos,
Binapine, BINAP, SegPhos, TunePhos.
Preferably, the transition metal precursors are one of following：[Ir(COD)Cl]2、[Ir(NBD)Cl]2、[Ir
(CH2CH2)2Cl]2；
Preferably, the chiral ligand is one of following：(R)-DTBM-SegPhos, (S)-DTBM-SegPhos.
The liquid chromatogram measuring condition of Biotin intermediate lactone II：Chiral OD-H columns；Column oven thermostatic 20
℃；Mobile phase：N-hexane：Isopropanol=70：30；Flow velocity：0.5mL/min；UV detectors：Detection wavelength 220nM.
The present invention is by meso cyclic acid anhydride under the effect of transition metal/chiral phosphine ligand, and in organic solvent plus hydrogen is gone pair
Titleization single step reaction, high yield, high-purity synthesize to obtain optical voidness (3aS, 6aR)-lactone, compared with the literature
(Org.Lett.2013,15,1740-1743), catalyst amount reduces by 50 times, and conversion ratio and stereoselectivity are higher.
The advantageous effect of the method for the present invention is mainly reflected in：Stereoselectivity is high, high conversion rate, high income, atom economy
Property it is high, at low cost, easy to operate, environmental pollution is small, is suitable for industrialized production.
Specific implementation mode
The content of present invention is better illustrated by following embodiment, but the present invention is not limited to following embodiments, in embodiment
Turn over number is the molar ratio of reaction substrate dosage and the dosage of catalyst.
Embodiment 1
Under argon atmosphere, 0.67mg [Ir (NBD) Cl] is weighed2It is dissolved in 1.0mL anaerobic tetrahydrofurans, then weighs again
1.62mg (R)-Binapine (being bought from Stream Reagent Companies) is added in solution, in argon atmospher, stirs half under room temperature
Hour, it is spare to obtain catalyst solution.
In the glove box full of argon atmospher, weighing 34mg biotin intermediate acid anhydrides I, (Zhejiang sage reaches biological medicine company share
Co., Ltd provides) in the peace equipped with magnetic stir bar falls bottle, catalyst solution well prepared in advance is then added, and be added
Peace bottle of falling is put into hydriding reactor by tetrahydrofuran, then the hydrogen of the argon gas in hydriding reactor is replaced three times, is then charged with 80bar
Hydrogen, be heated to 120 DEG C and react 24 hours, carefully deflate after cooling, then reaction solution is filtered out into catalyst by segment silica gel,
It is eluted with ethyl acetate (5mL), obtaining target product biology intermediate lactone II after reduced under vacuum, (conversion ratio is more than
99%, ee value 99%).
Embodiment 2
According to the method for embodiment 1, (R)-Binapine is replaced with other commercially available chiral ligands, other conditions are constant,
Desymmetrization reduction is carried out to biotin intermediate acid anhydrides I.The conversion ratio of the Biotin intermediate lactone II obtained by the reaction and
Stereoselectivity is shown in Table 1.In table 1,2,3, S/C is the molar ratio of reaction substrate and catalyst.
Table 1:The conversion results of different chiral ligands
The structural formula of part chiral ligand is as follows：
Table 1 the result shows that, catalyst amount be reaction substrate 1/100 under the conditions of, use chiral ligand (R)-
Outstanding conversion ratio and stereoselectivity can be obtained in DTBM-SegPhos, (S)-DTBM-SegPhos, is better than other chiral ligands,
It is also significantly better than C3-TunePhos.Therefore above two chiral ligand is preferred ligand.
Embodiment 3
According to the method for embodiment 2, tetrahydrofuran is replaced with other solvents, and the dosage of catalyst is adjusted to reaction bottom
The 1/5000 of object dosage, other conditions are constant, and desymmetrization reduction is carried out to biotin intermediate acid anhydrides I.This is obtained by the reaction
The conversion ratio and stereoselectivity of Biotin intermediate lactone II is shown in Table 2.
Table 2:The conversion results of different solvents
Table 2 the result shows that, under the conditions of catalyst amount is the 1/5000 of reaction substrate, consider conversion ratio and vertical
Body selectivity, for chiral ligand (R)-DTBM-SegPhos, tetrahydrofuran is better than other solvents；
Embodiment 4
According to the method for embodiment 2, (R)-Binapine is replaced with (S)-DTBM-SegPhos, and adjust addition catalyst
Amount, other conditions are constant, and desymmetrization reduction is carried out to biotin intermediate acid anhydrides I.Among the biotin obtained by the reaction
The conversion ratio and stereoselectivity of body lactone II are shown in Table 3.
Table 3:The reaction result of different turn over number
Table 3 the result shows that, under conditions of catalyst amount is reduced to the 1/100 of reaction substrate, 000, consider
Conversion ratio and stereoselectivity, chiral ligand (S)-DTBM-SegPhos are preferred ligand.
The above is only preferred embodiments of the present invention, not makees any form to the technology contents of the present invention
On limitation.All any simple modification, equivalent change and modification made to the above embodiment according to the technical essence of the invention,
It each falls in protection scope of the present invention.
Claims (5)
1. a kind of method of synthesizing optical Pure biotin intermediate lactone, it is characterised in that：
Using biotin intermediate acid anhydrides is reaction substrate shown in formula (I), in organic solvent, transition-metal catalyst is added,
Desymmetrization acid anhydrides reduction reaction occurs under 50-150bar atmosphere of hydrogen, under the conditions of 50-150 DEG C 6-72 hours, then filters
Except catalyst, optical voidness biotin intermediate (3aS, 6aR)-lactone shown in formula (II) is obtained after recrystallization；
Wherein formula (I) (II) is as follows：
The organic solvent is tetrahydrofuran, 1,4- dioxane or their mixture；
The chiral ligand of transition-metal catalyst is (R)-DTBM-SegPhos or (S)-DTBM-SegPhos, wherein (R)-
The structural formula of DTBM-SegPhos is as follows：
2. according to the method described in claim 1, it is characterized in that, reaction substrate initial concentration is 1- in the organic solvent
The addition of 700g/L, transition-metal catalyst are 20-1000mg/L.
3. according to the method described in claim 1, it is characterized in that, a concentration of 200-400g/L of reaction substrate.
4. method according to claim 1 or 2, which is characterized in that under the transition metal precursors of transition-metal catalyst are
One of row：[Ir(COD)Cl]2、[Ir(NBD)Cl]2、[Ir(CH2CH2)2Cl]2、[Ir(COD)2]X、[Ir(NBD)2] X, wherein X
For balance anion, it is selected from halogen, BF4、B(Ar)4、ClO4、SbF6、PF6Or CF3SO3。
5. method according to claim 1 or 2, which is characterized in that the preparation method of transition-metal catalyst is：In nitrogen
Under atmosphere, in organic solvent, transition metal precursors and chiral ligand are sequentially added, are stirred 0.25-3 hours at 10-50 DEG C,
Transition-metal catalyst is made.
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