CN106278932A - Ring-type α-dehydrogenation amido ketone, chiral ring α-amido ketone and preparation method thereof - Google Patents
Ring-type α-dehydrogenation amido ketone, chiral ring α-amido ketone and preparation method thereof Download PDFInfo
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- 0 CC(CC[C@@]1C)P1c1ccc(C*(c(ccc2c3OCO2)c3-c(c2*(cc3)OCO2)c3P*=C)=C)cc1P(CCC1)[C@]1N Chemical compound CC(CC[C@@]1C)P1c1ccc(C*(c(ccc2c3OCO2)c3-c(c2*(cc3)OCO2)c3P*=C)=C)cc1P(CCC1)[C@]1N 0.000 description 3
- XAFVQEWIADNYNL-UHFFFAOYSA-N CC(NC(C(c1c2)=O)=Cc1ccc2Br)=O Chemical compound CC(NC(C(c1c2)=O)=Cc1ccc2Br)=O XAFVQEWIADNYNL-UHFFFAOYSA-N 0.000 description 1
- CQGOWEDDIQZCJS-UHFFFAOYSA-O CC(NC(CC1)C2O[NH+]2C1=CC(F)=CCC=C)=O Chemical compound CC(NC(CC1)C2O[NH+]2C1=CC(F)=CCC=C)=O CQGOWEDDIQZCJS-UHFFFAOYSA-O 0.000 description 1
- UMVWGVTTZNAYPN-KRWDZBQOSA-N CC(N[C@@H](CC(C1=C2)=CCC=C2c2ccccc2)C1=O)=O Chemical compound CC(N[C@@H](CC(C1=C2)=CCC=C2c2ccccc2)C1=O)=O UMVWGVTTZNAYPN-KRWDZBQOSA-N 0.000 description 1
- YVMQPEGDBBLYKW-UHFFFAOYSA-N CCc1ccc(C=C(C2=O)NC(C)=O)c2c1 Chemical compound CCc1ccc(C=C(C2=O)NC(C)=O)c2c1 YVMQPEGDBBLYKW-UHFFFAOYSA-N 0.000 description 1
- RPKCLSMBVQLWIN-UHFFFAOYSA-N CNc1ccccc1N Chemical compound CNc1ccccc1N RPKCLSMBVQLWIN-UHFFFAOYSA-N 0.000 description 1
- HRWCWYGWEVVDLT-DTWKUNHWSA-N N[C@@H](Cc1ccccc11)[C@@H]1O Chemical compound N[C@@H](Cc1ccccc11)[C@@H]1O HRWCWYGWEVVDLT-DTWKUNHWSA-N 0.000 description 1
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Abstract
The present invention provides a kind of ring-type α-dehydrogenation amido ketone, a kind of chiral ring α-amido ketone and the preparation method of a kind of chiral ring α-amido ketone.The preparation method of the chiral ring α-amido ketone of the present invention is, in organic solvent, under the catalytic action of double phosphine-rhodium complexs, the ring-type α that following formula (1) represents-dehydrogenation amido ketone reacts under an atmosphere of hydrogen, obtains chiral ring α-amido ketone that following formula (2) represents.
Description
Technical field
The present invention relates to a kind of ring-type α-dehydrogenation amido ketone, a kind of chiral ring α-amido ketone,
And the preparation method of a kind of chiral ring α-amido ketone.Chiral ring α-amido the ketone of the present invention
Preparation method be a kind of under double phosphines-Rhodium Complexes Catalyzed effect, use asymmetric catalytic hydrogenation skill
Art prepares the synthetic method of chiral ring α-amido ketone.
Background technology
Chiral ring α-amido ketone skeleton is widely present in multi-medicament molecule and physiologically active molecule
In, it may be additionally used for synthesis of chiral cyclic aminocarbonyl alcohol part and the medicine of chiral ring amine simultaneously
Intermediate.
At present chiral ring α-amido ketone be mainly obtained by chirality chain α-amino acid point
Friedel-crafts acylation ((a) D.E.McClure, B.H.Arison, J.H.Jones, J.J. in son
Baldwin,J.Org.Chem.1981,46,2431-2433.(b)M.Kurokawa,T.
Watanabe, T.Ishikawa, Helv.Chim.Acta 2007,90,574-587.) or cyclic ketone
Asymmetric α-amido reaction ((a) Y.Yamashita, H.Ishitani, S.Kobayashi, Can.J.
Chem.2000,78,666-672.(b)N.Kumaragurubaran,K.Juhl,W.Zhuang,A.K.A.J.Am.Chem.Soc.2002,124,6254-6255.(c)Y.
Hayashi,S.Aratake,Y.Imai,K.Hibino,Q.-Y.Chen,J.Yamaguchi,T.
Uchimaru, Chem.Asian J.2008,3,225-232.), but there is efficiency in these methods
Low, Atom economy is poor, not environmentally etc. shortcoming and be difficult to industrialization.And due to product chirality
Ring-type α-amido ketone is unstable under the conditions of Acidity of Aikalinity, and easy racemization, so above-mentioned comparison is harsh
Reaction condition under would become hard to obtain the product of high enantioselectivity.
Summary of the invention
In order to solve above-mentioned the above-mentioned problems in the prior art, it is the most right that the present invention uses first
The technology claiming the ring-type α of catalytic hydrogenation-dehydrogenation amido ketone achieves the efficient of chiral ring α-amido ketone
Synthesis.The preparation method of the chiral ring α-amido ketone according to the present invention, combined coefficient is carried
Height, enantio-selectivity is high, and Atom economy is good, reduce synthesis cost, and does not exists
Racemization problem, thus it is expected to realize the industrialization synthesis of chiral ring α-amido ketone.
The present invention relates to following content.
<1>a kind of ring-type α-dehydrogenation amido ketone, it is the compound represented such as following formula (1),
Wherein, R is selected from hydrogen atom, C1-C6 alkyl, phenyl, substituted-phenyl, C1-C7
Acyl group, C1-C7 alkoxy acyl, hydroxyl, C1-C7 alkoxyl, C1-C7 acyloxy, amino,
Single (C1-C7 alkyl) amido, two (C1-C7 alkyl) amido, C1-C7 amide groups, front three
Base is silica-based, dihydroxy boryl, diphenylphosphine epoxide, phenylmercapto, fluorine atom, chlorine atom,
One or more in bromine atoms, atomic iodine.
<2>a kind of chiral ring α-amido ketone, it is the compound represented such as following formula (2),
Wherein, R is selected from hydrogen atom, C1-C6 alkyl, phenyl, substituted-phenyl, C1-C7
Acyl group, C1-C7 alkoxy acyl, hydroxyl, C1-C7 alkoxyl, C1-C7 acyloxy, amino,
Single (C1-C7 alkyl) amido, two (C1-C7 alkyl) amido, C1-C7 amide groups, front three
Base is silica-based, dihydroxy boryl, diphenylphosphine epoxide, phenylmercapto, fluorine atom, chlorine atom,
One or more in bromine atoms, atomic iodine,
Be designated as chiral carbon, it is R configuration or S configuration.
<3>preparation method of a kind of chiral ring α-amido ketone, it is characterised in that:
In organic solvent, under the catalytic action of double phosphine-rhodium complexs, following formula (1) table
The ring-type α shown-dehydrogenation amido ketone reacts under an atmosphere of hydrogen, obtains following formula (2) table
Chiral ring α-amido the ketone shown,
Wherein, R be selected from hydrogen, C1-C6 alkyl, phenyl, substituted-phenyl, C1-C7 acyl group,
C1-C7 alkoxy acyl, hydroxyl, C1-C7 alkoxyl, C1-C7 acyloxy, amino, list (C1-C7
Alkyl) amido, two (C1-C7 alkyl) amido, C1-C7 amide groups, trimethyl be silica-based, two
Dihydroxyboryl, diphenylphosphine epoxide, phenylmercapto, fluorine atom, chlorine atom, bromine atoms, iodine
One or more in atom,
In formula (2), the be designated as chiral carbon of *, it is R configuration or S configuration.
In the preparation method of the chiral ring α-amido ketone of the present invention, described pair of phosphine-rhodium complex
It is the coordination compound represented by formula [Rh (L) (L ')] X, wherein,
L be selected from following (R)-BINAP, (R)-Segphos, (R, R)-QuinoxP*,
(R, R)-Duphos, (S, S)-BenzP*, (R, R)-Miniphos, (S)-TCFP and theirs is right
Reflect any one chiral diphosphine ligand in isomer:
L ' is for joining selected from pungent two any one auxiliary dienes dilute or 2,5-norbornadiene of 1,5-ring
Body, X is selected from SbF6 -Or BF4 -Any one anion.
In the preparation method of the chiral ring α-amido ketone of the present invention, described pair of phosphine-rhodium complex
The molar ratio of the ring-type α-dehydrogenation amido ketone represented with formula (1) is, double phosphine-rhodium complexs/
Ring-type α-dehydrogenation amido ketone=1/100～1/20000 that formula (1) represents.
In the preparation method of the chiral ring α-amido ketone of the present invention, described organic solvent is choosing
From ethyl acetate, dichloromethane, oxolane, methanol, ethanol, isopropanol, trifluoroethanol
In any one or two or more.
In the preparation method of the chiral ring α-amido ketone of the present invention, Hydrogen Vapor Pressure is 1～100
Bar, reaction temperature is 0～50 DEG C, and the response time is 1～48 hour.
To sum up, chiral ring α-amido ketone that the formula (2) related in the present invention represents, be by
The ring-type α that the formula (1) related in the present invention represents-dehydrogenation amido ketone is as raw material (below,
Sometimes referred to as " substrate ") obtain.It addition, according to the chiral ring α-amido ketone of the present invention
Preparation method, combined coefficient is improved, and enantio-selectivity is high, and Atom economy is good, fall
Low synthesis cost.Further, chiral ring α-amine that preparation in accordance with the present invention obtains
Base ketone, can be used for synthesis of chiral cyclic aminocarbonyl alcohol part and the pharmaceutical intermediate of chiral ring amine.
Detailed description of the invention
In the preparation method of the chiral ring α-amido ketone of the present invention, formula (1) before and after reaction
And the R in formula (2) does not changes.
In formula (1) and formula (2), R is selected from hydrogen atom, C1-C6 alkyl, benzene
Base, substituted-phenyl, C1-C7 acyl group, C1-C7 alkoxy acyl, hydroxyl, C1-C7 alkoxyl,
C1-C7 acyloxy, amino, list (C1-C7 alkyl) amido, two (C1-C7 alkyl) amido,
C1-C7 amide groups, trimethyl are silica-based, dihydroxy boryl, diphenylphosphine epoxide, phenylmercapto,
In fluorine atom, chlorine atom, bromine atoms, atomic iodine any one or two or more.Wherein,
As C1-C6 alkyl, can enumerate methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl,
Isobutyl group, the tert-butyl group, n-pentyl, isopentyl, neopentyl, hexyl etc.；Alternatively phenyl,
2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, 2-methoxyphenyl, 3-first can be enumerated
Phenyl, 4-methoxyphenyl, 2-ethoxyl phenenyl, 3-ethoxyl phenenyl, 4-ethoxybenzene
Base, 2-difluorophenyl, 3-difluorophenyl, 4-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl,
4-chlorophenyl, 2-bromo phenyl, 3-bromo phenyl, 4-bromo phenyl, 2-iodine substituted phenyl, 3-
Iodine substituted phenyl, 4-iodine substituted phenyl, 1-naphthyl, 2-naphthyl, 2-trifluoromethyl, 3-fluoroform
Base phenyl, 4-trifluoromethyl, 2-furyl, 2-thienyl, 3,4-Dimethoxyphenyl,
3,4-3,5-dimethylphenyl, 3,4-Dichlorobenzene base, 3,4-methylene phenyl etc.；As C1-C7 acyl
Base, can enumerate formoxyl, acetyl group, propiono, bytyry, valeryl, caproyl,
Heptanoyl group etc.；As C1-C7 alkoxy acyl, can enumerate methoxy acyl group, ethoxy acyl group, third
Oxygen acyl group, fourth oxygen acyl group, penta oxygen acyl group, own oxygen acyl group, oxygen acyl group in heptan etc.；As C1-C7
Alkoxyl, can enumerate methoxyl group, ethyoxyl, propoxyl group, butoxy, amoxy, own oxygen
Base, epoxide in heptan etc.；As C1-C7 acyloxy, can enumerate formyloxy, acetoxyl group,
Propionyloxy, butyryl acyloxy, valeryl epoxide, hexylyloxy, oenanthyl epoxide etc.；As list (C1-C7
Alkyl) amido, monomethyl amido, MEA base, single propyl group amido, only son can be enumerated
Base amido, single amyl group amido, single hexyl amido, single heptyl amido etc.；As two (C1-C7
Alkyl) amido, dimethyl amido, diethyl amido, dipropyl amido, two fourths can be enumerated
Two alkyl of base amido, diamyl amido, dihexyl amido, diheptyl amido etc. are identical
Two (C1-C7 alkyl) amido, and Methylethyl amido, ethyl propyl amido, methyl-propyl
Two (C1-C7 alkyl) amido that two alkyl of amido etc. are different；As C1-C7 amide groups,
Can enumerate formamido, acetamido, propionamido-, amide-based small, valeryl amido, oneself
Amide groups, heptanamido etc..
It addition, in formula (1) and formula (2), Ph-R group also may indicate that naphthyl.
In formula (1) and formula (2), R can be single replacement, it is also possible to be two
Replacement, three replacements or four replacements.Represent that " two replacements or three replacements or four take at R
Generation " in the case of, the implication that the implication that each substituent R represents represents with above-mentioned R is identical,
Further, each R is identical group respectively or is different groups respectively.When Ph-R group table
When showing naphthyl, it is exactly a kind of mode of " R is two replacements ".
The preparation method is that and carry out under the catalytic action of double phosphine-rhodium complexs.The present invention
In, double phosphine-rhodium complexs can represent with [Rh (L) (L ')] X.Wherein, can arrange as L
Lift following (R)-BINAP, (R)-Segphos, (R, R)-QuinoxP*, (R, R)-Duphos,
(S, S)-BenzP*, (R, R)-Miniphos, (S)-TCFP:
, and their enantiomer, i.e. (S)-BINAP, (S)-Segphos, (S, S)-QuinoxP*,
(S,S)-Duphos、(R,R)-BenzP*、(S,S)-Miniphos、(R)-TCFP；Permissible as L '
Enumerate the pungent two dilute or 2,5-norbornadienes of 1,5-ring；SbF can be enumerated as X6 -Or BF4 -。
In the preparation method of the present invention, for Hydrogen Vapor Pressure, there is no particular limitation, as long as can
Carry out the catalytic asymmetric hydrogenation of the present invention.But, from reaction yield and reaction
From the viewpoint of efficiency, the Hydrogen Vapor Pressure of atmosphere of hydrogen be set as 1～100bar, preferably 1～
50bar, more preferably 1～20bar.
In the preparation method of the present invention, for organic solvent, there is no particular limitation, as long as this has
Machine solvent can dissolve reaction raw materials, and make the catalytic asymmetric hydrogenation of the present invention enter
Row.But, from the viewpoint of reaction yield and reaction efficiency, organic solvent is preferred
It it is polar solvent.Wherein, preferably from ethyl acetate, dichloromethane, oxolane, methanol,
One or more solvents selected in ethanol, isopropanol, trifluoroethanol.As two kinds with
The mixed solvent of upper solvent, as long as selecting solvent species and proportioning as suitably desired,
It is not particularly limited.
The preparation method of the present invention can use alr mode to carry out, and does not has spy for mixing speed
Do not limit, as long as the reaction of the present invention can be carried out.
In the preparation method of the present invention, to reaction temperature and response time the most particularly limit
It is fixed, as long as the reaction of the present invention can be carried out.But, from reaction yield and reaction effect
From the viewpoint of rate, reaction temperature can be set as 0～50 DEG C, preferably 25～50 DEG C, more excellent
Select 25～30 DEG C；Further, the response time can be set as 1～48 hour, preferably 1～24 hour,
More preferably 1～12 hour, further preferred 1～6 hour.
Preferred in the preparation process in accordance with the present invention, when calculating with mol ratio, (biphosphine ligand-rhodium coordinates
The ring-type α that thing/formula (1) represents-dehydrogenation amido ketone) be 1/100～1/20000, preferably 1/500～
1/20000, more preferably 1/1000～1/20000, further preferred 1/2000～1/20000, special
The most preferably 1/10000～1/20000.
The main types of chiral ring α-amido ketone that preparation in accordance with the present invention obtains be by
The configuration of the catalyst (that is, biphosphine ligand-rhodium complex) used in preparation method is determined
's.In other words, in the case of the configuration of catalyst determines, preparation in accordance with the present invention
The main types of the product obtained also determines that.The product that preparation in accordance with the present invention obtains
The main types of thing (that is, chiral ring α-amido ketone that formula (2) represents) be R configuration or
Person's S configuration.
Compared with the preparation method of existing chiral ring α-amido ketone, preparation method of the present invention has
Reaction condition is gentle, and post processing is easy, and chiral catalyst is readily synthesized and stable in properties, substrate
The suitability is strong, and the productivity of product such as increases substantially at the advantage.It addition, according to the preparation of the present invention
Method, the enantiomeric excess of product can reach 99%, and optical purity is high.The present invention is
Industrialized production chiral ring α-amido ketone provides feasible method.
Embodiment:
Below the preparation method of the present invention is provided specific embodiment.Obviously, the protection of the present invention
Scope is not limited to following embodiment.
In the examples below, ring-type α formula (1) represented-dehydrogenation amido ketone 1a, 1b,
1c, 1d, 1e, 1f, 1g, 1h, 1i, 1j, 1k, 1l, 1m represent；By formula (2) table
Show chiral ring α-amido ketone 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k,
2l, 2m represent.
It addition, as it has been described above, in the preparation method of the chiral ring α-amido ketone of the present invention,
Before and after reaction, the R in formula (1) and formula (2) does not changes, so, do not say and
Analogy, in the examples below, substrate 1a, 1b, 1c, 1d, 1e, 1f, 1g, 1h, 1i, 1j,
1k, 1l, 1m (that is, ring-type α-dehydrogenation amido ketone that formula (1) represents) are under an atmosphere of hydrogen
After reacting, be correspondingly made available chiral ring α-amido ketone 2a, 2b, 2c, 2d, 2e, 2f,
2g、2h、2i、2j、2k、2l、2m。
In the examples below, for simplicity, by 1, pungent two dilute referred to as " cod " of 5-ring, will
2,5-norbornadiene is referred to as " nbd ".
In the examples below, productivity is to carry out calculated numerical value according to formula calculated below.
It addition, enantiomeric excess (hereinafter referred to as " ee value ") is by following in theory
Formula is calculated:
Enantiomeric excess %={ | [S]-[R]/([S]+[R]) } × 100%
Wherein [S] is the amount of S configuration enantiomer product, and [R] is the amount of R configuration enantiomer product.
In the examples below, enantiomeric excess is to survey with HPLC (high performance liquid chromatography)
, for carrying out the LC-2010 that the instrument of HPLC measurement is Shimadzu Corporation, use Japan
The chiral chromatographic column that Daicel company produces.
It addition, in the examples below, for each product after synthesis, namely for
Each ring-type α after synthesis-dehydrogenation amido ketone and chiral ring α-amido ketone (that is, Mei Getong
The compound that formula (1) and formula (2) represent), all it was NMR and analyzed, but for
Same products, for simplicity, only specifically record occurring for the first time when, later
Record is omitted.
In following example and application examples, for carrying out the instrument of nuclear magnetic resonance spectroscopy it is
The Mercury Plus-400 of Varian company (400MHz,1H；100MHz,13C)
Spectrometer.In following application examples, the instrument measured for specific rotatory power is Rudolph
Research Analytical Autopol VI Automatic Polarimeter (uses detection optical wavelength
For 589nm, optical path length is 50mm)
Embodiment 1:
Preparation embodiment
In the two-mouth bottle of 500mL, add aluminum trichloride (anhydrous) (AlCl3) 12mmol, then
Adding 60mml tetrachloroethylene solvent, mixture stirs 1 hour at normal temperatures, then in stirring
Under, it is slow added into four dissolved with 4-phenylmethylene-2-methyl-5 (4H)-oxazolone 36mmol
Vinyl chloride solution 60mL, after adding all of tetrachloroethylene solution, reacting by heating solution,
At 100 DEG C, stirring reaction 1 hour, then returns back to room temperature and stirs 2 hours.After reaction terminates,
Add the 1mol/L dilute hydrochloric acid solution of 120mL, stir 10 minutes, extract organic layer, use
Dichloromethane washes twice aqueous phase, merges organic facies, and rotation is evaporated off solvent, and residue is through column chromatography
Separation can obtain clean product 1a.Product 1a directly uses after dichloromethane and petroleum ether recrystallization again
In hydrogenation.
The determination data of 1a is as follows.
1H NMR(400MHz,CDCl3) δ: 2.19 (s, 3H), 6.95 (d, J=7.2Hz, 1H),
7.02-7.07(m,1H),7.26-7.31(m,1H),7.32-7.35(m,1H),7.48(br s,1H),
7.48(s,1H)；
13C NMR(100MHz,CDCl3)δ:24.1,122.3,123.6,124.6,127.3,
127.4,132.0,135.6,147.0,169.0,193.8.
Embodiment 2:
Preparation embodiment
In the reaction tube of 50mL, it is separately added into 2.8mg's
[Rh((R)-BINAP)(nbd)]SbF6Catalyst, the substrate 1a of 56mg [substrate: catalyst=
100:1 (mol ratio)], reaction tube is placed in hydriding reactor, evacuation changes hydrogen three times,
Under hydrogen shield, add the methanol of 2mL degassing, finally Hydrogen Vapor Pressure is adjusted to 100bar,
It is stirred vigorously at 50 DEG C 1 hour, stopped reaction, concentrates solvent evaporated, obtain white solid product
2a, the productivity of product 2a is 99%.
The determination data of 2a is as follows.
1H NMR(400MHz,CDCl3): δ 2.08 (s, 3H), 2.96 (dd, J=5.6Hz, 16.8
Hz, 1H), 3.75 (dd, J=8.2Hz, 16.4Hz, 1H), 4.52-4.58 (m, 1H), 6.39 (br s,
1H), 7.39 (t, J=7.6Hz, 1H), 7.45 (d, J=7.6Hz, 1H), 7.63 (t, J=7.6Hz,
1H), 7.75 (d, J=7.6Hz, 1H)；
13C NMR(100MHz,CDCl3):δ23.2,35.1,56.8,124.4,126.9,128.1,
134.9,135.9,151.7,171.0,203.6.
Carry out HPLC survey timing condition as follows.Use the DAICEL that Daicel company of Japan produces
Chiralpak IE chiral chromatographic column, flowing is normal hexane/isopropanol (volume ratio)=80/20 mutually,
Flow rate of mobile phase is 1.0mL/min, and detection wavelength is 254nm, tmajor=21.8min, tminor=
19.2min.Product 2a is configured as S.HPLC measurement result, the ee value of 2a is 81%.
Embodiment 3:
Preparation embodiment
In the reaction tube of 50mL, it is separately added into 2.8mg's
[Rh((R)-Segphos)(nbd)]SbF6Catalyst, the substrate 1a of 56mg [substrate: catalyst=
100:1 (mol ratio)], reaction tube is placed in hydriding reactor, evacuation changes hydrogen three times,
Under hydrogen shield, add the ethanol of 2mL degassing, finally Hydrogen Vapor Pressure is adjusted to 3bar,
It is stirred vigorously at 25 DEG C 1 hour, stopped reaction, concentrates solvent evaporated, obtain white solid product
2a, the productivity of product 2a is 99%.Carry out HPLC survey according to the same manner as in Example 2
Fixed.The ee value being configured as S, 2a of product 2a is 53%.
Embodiment 4:
Preparation embodiment
In the reaction tube of 50mL, it is separately added into 2.2mg's
[Rh((R,R)-Duphos)(cod)]BF4Catalyst, the substrate 1a of 56mg [substrate: catalyst=
100:1 (mol ratio)], reaction tube is placed in hydriding reactor, evacuation changes hydrogen three times,
Under hydrogen shield, add the isopropanol of 2mL degassing, finally Hydrogen Vapor Pressure be adjusted to 30bar,
It is stirred vigorously at 50 DEG C 12 hours, stopped reaction, concentrates solvent evaporated, obtain white solid
Product 2a, the productivity of product 2a is 99%.Carry out HPLC according to the same manner as in Example 2
Measure, the difference is that only tmajor=19.0min, tminor=21.6min.The structure of product 2a
Type be the ee value of R, 2a be 65%.
Embodiment 5:
Preparation embodiment
The reaction tube of 50mL is separately added into 2.3mg [Rh ((R, R)-
QuinoxP*)(cod)]SbF6Catalyst, the substrate 1a of 112mg [substrate: catalyst=200:
1 (mol ratio)], reaction tube is placed in hydriding reactor, evacuation changes hydrogen three times, at hydrogen
The lower ethyl acetate adding 2mL degassing of protection, is finally adjusted to 50bar, at 0 DEG C by Hydrogen Vapor Pressure
Under be stirred vigorously 24 hours, stopped reaction, concentrate solvent evaporated, obtain white solid product 2a,
The productivity of product 2a is 99%.Carry out HPLC mensuration according to the same manner as in Example 4,
The ee value being configured as R, 2a of product 2a is 71%.
Embodiment 6:
Preparation embodiment
The reaction tube of 50mL is separately added into 1.7mg [Rh ((S, S)-
BenzP*)(cod)]SbF6Catalyst, the substrate 1a [substrate: catalyst=500:1 of 280mg
(mol ratio)], reaction tube is placed in hydriding reactor, evacuation changes hydrogen three times, at hydrogen
The lower oxolane adding 2mL degassing of protection, is finally adjusted to 10bar, at 0 DEG C by Hydrogen Vapor Pressure
Under be stirred vigorously 48 hours, stopped reaction, concentrate solvent evaporated, obtain white solid product 2a,
The productivity of product 2a is 99%.Carry out HPLC mensuration according to the same manner as in Example 2.
The ee value being configured as S, 2a of product 2a is 79%.
Embodiment 7:
Preparation embodiment
The reaction tube of 300mL is separately added into 1.5mg [Rh ((R, R)-
Miniphos) (cod)] SbF6 catalyst, the substrate 1a of 11.2g [substrate: catalyst=20000:
1 (mol ratio)], reaction tube is placed in hydriding reactor, evacuation changes hydrogen three times, at hydrogen
The lower dichloromethane adding 30mL degassing of protection, is finally adjusted to 1bar, at 25 DEG C by Hydrogen Vapor Pressure
Under be stirred vigorously 6 hours, stopped reaction, concentrate solvent evaporated, obtain white solid product 2a,
The productivity of product 2a is 99%.Carry out HPLC mensuration according to the same manner as in Example 4.
The ee value being configured as R, 2a of product 2a is 92%.
Embodiment 8:
Preparation embodiment
The reaction tube of 300mL is separately added into 1.5mg [Rh ((S)-
TCFP)(cod)]SbF6Catalyst, the substrate 1a [substrate: catalyst=10000:1 of 5.6g
(mol ratio)], reaction tube is placed in hydriding reactor, evacuation changes hydrogen three times, at hydrogen
The lower trifluoroethanol adding 12mL degassing of protection, is finally adjusted to 20bar by Hydrogen Vapor Pressure,
It is stirred vigorously at 30 DEG C 1 hour, stopped reaction, concentrates solvent evaporated, obtain white solid product
2a, the productivity of product 2a is 99%.Carry out HPLC survey according to the same manner as in Example 2
Fixed.The ee value being configured as S, 2a of product 2a is 98%.
Embodiment 9:
Preparation embodiment
[Rh ((R)-TCFP) (cod)] SbF of 1.5mg it is separately added in the reaction tube of 300mL6
Catalyst, the substrate 1a [substrate: catalyst=10000:1 (mol ratio)] of 5.6g, will be anti-
Answering test tube to be placed in hydriding reactor, evacuation changes hydrogen three times, adds 12mL under hydrogen shield
The trifluoroethanol of degassing, is finally adjusted to 20bar by Hydrogen Vapor Pressure, is stirred vigorously 1 at 30 DEG C
Hour, stopped reaction, concentrate solvent evaporated, obtain white solid product 2a, the productivity of product 2a
It is 99%.Carrying out HPLC mensuration according to the same manner as in Example 4, product 2a is configured as
The ee value of R, 2a is 98%.
Embodiment 10:
Preparation embodiment
In the two-mouth bottle of 500mL, add aluminum trichloride (anhydrous) (AlCl3) 12mmol, then
Adding 60mml tetrachloroethylene solvent, mixture stirs 1 hour at normal temperatures, then in stirring
Under, it is slow added into dissolved with 4-(2-aminomethyl phenyl) methylene-2-methyl-5 (4H)-oxazolone
The tetrachloroethylene solution 60mL of 36mmol, after adding all of tetrachloroethylene solution, heating
Reaction solution, at 100 DEG C, stirring reaction 1 hour, then returns back to room temperature and stirs 2 hours.
After reaction terminates, add the 1mol/L dilute hydrochloric acid solution of 120mL, stir 10 minutes, extraction
Going out organic layer, wash twice aqueous phase with dichloromethane, merge organic facies, rotation is evaporated off solvent, residual
Excess can obtain clean product 1b through column chromatography for separation.Product 1b is again through dichloromethane and petroleum ether weight
Hydrogenation it is directly used in after crystallization.
The determination data of 1b is as follows.
1H NMR(400MHz,CDCl3) δ: 2.20 (s, 3H), 2.23 (s, 3H), 6.94 (t, J=
7.2Hz, 1H), 7.07 (d, J=8.0Hz, 1H), 7.16 (d, J=7.2Hz, 1H), 7.53 (br s,
1H),7.57(s,1H)；
13C NMR(100MHz,CDCl3)δ:17.3,24.1,121.2,123.0,127.1,127.2,
131.3,131.6,137.4,144.7,168.8,194.0.
Embodiment 11:
Preparation embodiment
The reaction tube of 300mL is separately added into 1.5mg [Rh ((S)-
TCFP)(cod)]SbF6Catalyst, the substrate 1b [substrate: catalyst=10000:1 of 6.0g
(mol ratio)], reaction tube is placed in hydriding reactor, evacuation changes hydrogen three times, at hydrogen
The lower trifluoroethanol adding 12mL degassing of protection, is finally adjusted to 20bar by Hydrogen Vapor Pressure,
It is stirred vigorously at 30 DEG C 1 hour, stopped reaction, concentrates solvent evaporated, obtain white solid product
2b, the productivity of product 2b is 99%.
The determination data of 2b is as follows.
1H NMR(400MHz,CDCl3): δ 2.08 (s, 3H), 2.40 (s, 3H), 2.89 (dd, J=
5.6Hz, 16.4Hz, 1H), 3.70 (dd, J=8.0Hz, 16.8Hz, 1H), 4.50-4.56 (m, 1H),
6.31 (br s, 1H), 7.32 (d, J=7.6Hz, 1H), 7.44 (d, J=7.6Hz, 1H), 7.54 (s,
1H)；
13C NMR(100MHz,CDCl3):δ21.3,23.2,34.8,57.0,124.3,126.6,
134.9,137.2,138.1,149.0,171.0,203.8.
Carry out HPLC survey timing condition as follows.Use the DAICEL that Daicel company of Japan produces
Chiralpak IE chiral chromatographic column, flowing is normal hexane/isopropanol (volume ratio)=80/20 mutually,
Flow rate of mobile phase is 1.0mL/min, and detection wavelength is 254nm, tmajor=23.8min, tminor=
20.1min.The ee value being configured as S, 2b of product 2b is 99%.
Embodiment 12:
Preparation embodiment
In the two-mouth bottle of 500mL, add aluminum trichloride (anhydrous) (AlCl3) 12mmol, then
Adding 60mml tetrachloroethylene solvent, mixture stirs 1 hour at normal temperatures, then in stirring
Under, it is slow added into dissolved with 4-(3-aminomethyl phenyl) methylene-2-methyl-5 (4H)-oxazolone
The tetrachloroethylene solution 60mL of 36mmol, after adding all of tetrachloroethylene solution, heating
Reaction solution, at 100 DEG C, stirring reaction 1 hour, then returns back to room temperature and stirs 2 hours.
After reaction terminates, add the 1mol/L dilute hydrochloric acid solution of 120mL, stir 10 minutes, extraction
Going out organic layer, wash twice aqueous phase with dichloromethane, merge organic facies, rotation is evaporated off solvent, residual
Excess can obtain clean product 1c through column chromatography for separation.Product 1c is again through dichloromethane and petroleum ether weight
Hydrogenation it is directly used in after crystallization.
The determination data of 1c is as follows.
1H NMR(400MHz,CDCl3)δ:2.18(s,3H),2.27(s,3H),6.70-6.80
(m, 2H), 7.09 (t, J=7.6Hz, 1H), 7.37 (s, 1H), 7.66 (s, 1H)；
13C NMR(100MHz,CDCl3)δ:17.6,22.3,120.2,123.7,124.0,127.2,
131.6,134.8,146.8,147.5,193.3.
Embodiment 13:
Preparation embodiment
The reaction tube of 300mL is separately added into 1.5mg [Rh ((S, S)-
Miniphos)(cod)]SbF6Catalyst, the substrate 1c of 12.0g [substrate: catalyst=20000:
1 (mol ratio)], reaction tube is placed in hydriding reactor, evacuation changes hydrogen three times, at hydrogen
The lower dichloromethane adding 30mL degassing of protection, is finally adjusted to 1bar, at 25 DEG C by Hydrogen Vapor Pressure
Under be stirred vigorously 6 hours, stopped reaction, concentrate solvent evaporated, obtain white solid product 2c,
The productivity of product 2c is 99%.
The determination data of 2c is as follows.
1H NMR(400MHz,CDCl3): δ 2.08 (s, 1H), 2.33 (s, 1H), 2.81 (dd, J=
5.2Hz, 16.8Hz, 1H), 3.72 (dd, J=8.0Hz, 16.8Hz, 1H), 4.50-4.55 (m, 1H),
6.29 (br s, 1H), 7.30 (t, J=7.6Hz, 1H), 7.44 (d, J=7.6Hz, 1H), 7.59 (d, J
=7.6Hz, 1H)；
13C NMR(100MHz,CDCl3):δ18.0,23.2,34.0,56.8,121.8,128.2,
134.6,136.2,136.4,150.8,171.1,204.0。
Carry out HPLC survey timing condition as follows.Use the DAICEL that Daicel company of Japan produces
Chiralpak IE chiral chromatographic column, flowing is normal hexane/isopropanol (volume ratio)=85/15 mutually, inspection
Survey wavelength is 254nm, 1.0mL/min, tmajor=27.8min, tminor=25.3min.Product 2c
The ee value being configured as S, 2c be 99%.
Embodiment 14:
Preparation embodiment
In the two-mouth bottle of 500mL, add aluminum trichloride (anhydrous) (AlCl3) 12mmol, then
Adding 60mml tetrachloroethylene solvent, mixture stirs 1 hour at normal temperatures, then in stirring
Under, it is slow added into dissolved with 4-(3-aminomethyl phenyl) methylene-2-methyl-5 (4H)-oxazolone
The tetrachloroethylene solution 60mL of 36mmol, after adding all of tetrachloroethylene solution, heating
Reaction solution, at 100 DEG C, stirring reaction 1 hour, then returns back to room temperature and stirs 2 hours.
After reaction terminates, add the 1mol/L dilute hydrochloric acid solution of 120mL, stir 10 minutes, extraction
Going out organic layer, wash twice aqueous phase with dichloromethane, merge organic facies, rotation is evaporated off solvent, residual
Excess can obtain clean product 1d through column chromatography for separation.Product 1d is again through dichloromethane and petroleum ether weight
Hydrogenation it is directly used in after crystallization.
The determination data of 1d is as follows.
1H NMR(400MHz,CDCl3)δ:2.18(s,3H),2.40(s,3H),6.70-6.80
(m, 2H), 7.17 (d, J=7.2Hz, 1H), 7.37 (s, 1H), 7.70 (s, 1H)；
13C NMR(100MHz,CDCl3)δ:17.6,24.1,123.5,123.8,124.9,127.2,
131.6,134.8,138.6,147.2,168.9,194.5.
Embodiment 15:
Preparation embodiment
The reaction tube of 300mL is separately added into 1.5mg [Rh ((S)-
TCFP)(cod)]SbF6Catalyst, the substrate 1d [substrate: catalyst=10000:1 of 6.0g
(mol ratio)], reaction tube is placed in hydriding reactor, evacuation changes hydrogen three times, at hydrogen
The lower ethyl acetate adding 12mL degassing of protection, is finally adjusted to 10bar by Hydrogen Vapor Pressure,
It is stirred vigorously at 30 DEG C 1 hour, stopped reaction, concentrates solvent evaporated, obtain white solid product
2d, the productivity of product 2d is 99%.
The determination data of 2d is as follows.
1H NMR(400MHz,CDCl3): 2.08 (s, 3H), 2.60 (s, 3H), 2.90 (dd, J=
5.6Hz, 16.4Hz, 1H), 3.70 (dd, J=8.0Hz, 16.8Hz, 1H), 4.45-4.55 (m, 1H),
6.37 (br s, 1H), 7.13 (d, J=8.0Hz, 1H), 7.26 (d, J=6.8Hz, 1H), 7.47 (t, J
=7.6Hz, 1H)；
13C NMR(100MHz,CDCl3):δ18.5,23.2,34.8,56.8,124.2,127.2,
129.4,132.4,135.2,147.4,171.1,203.1.
Carry out HPLC survey timing condition as follows.Use the DAICEL that Daicel company of Japan produces
Chiralpak IE chiral chromatographic column, flowing is normal hexane/isopropanol (volume ratio)=85/15 mutually, stream
Dynamic phase flow velocity is 1.0mL/min, and detection wavelength is 254nm, tmajor=50.5min, tminor=
41.1min.The ee value being configured as S, 2d of product 2d is 99%.
Embodiment 16:
Preparation embodiment
In the two-mouth bottle of 500mL, add aluminum trichloride (anhydrous) (AlCl3) 12mmol, then
Adding 60mml tetrachloroethylene solvent, mixture stirs 1 hour at normal temperatures, then in stirring
Under, it is slow added into dissolved with 4-(4-aminomethyl phenyl) methylene-2-methyl-5 (4H)-oxazolone
The tetrachloroethylene solution 60mL of 36mmol, after adding all of tetrachloroethylene solution, heating
Reaction solution, at 100 DEG C, stirring reaction 1 hour, then returns back to room temperature and stirs 2 hours.
After reaction terminates, add the 1mol/L dilute hydrochloric acid solution of 120mL, stir 10 minutes, extraction
Going out organic layer, wash twice aqueous phase with dichloromethane, merge organic facies, rotation is evaporated off solvent, residual
Excess can obtain clean product 1e through column chromatography for separation.Product 1e is again through dichloromethane and petroleum ether weight
Hydrogenation it is directly used in after crystallization.
The determination data of 1e is as follows.
1H NMR(400MHz,CDCl3) δ: 2.20 (s, 3H), 2.28 (s, 3H), 6.82 (d, J=
8.0Hz, 1H), 7.07 (d, J=8.0Hz, 1H), 7.15 (s, 1H), 7.46 (s, 1H), 7.51 (br s,
1H)；
13C NMR(100MHz,CDCl3)δ:21.3,24.0,122.1,124.7,124.9,127.7,
131.4,135.3,137.3,143.9,168.7,194.0.
Embodiment 17:
Preparation embodiment
The reaction tube of 300mL is separately added into 1.5mg [Rh ((S, S)-
Miniphos)(cod)]SbF6Catalyst, the substrate 1e of 12.0g [substrate: catalyst=20000:
1 (mol ratio)], reaction tube is placed in hydriding reactor, evacuation changes hydrogen three times, at hydrogen
The lower dichloromethane adding 30mL degassing of protection, is finally adjusted to 5bar, at 25 DEG C by Hydrogen Vapor Pressure
Under be stirred vigorously 4 hours, stopped reaction, concentrate solvent evaporated, obtain white solid product 2e,
The productivity of product 2e is 99%.
The determination data of 2e is as follows.
1H NMR(400MHz,CDCl3): 2.08 (s, 3H), 2.60 (s, 3H), 2.90 (dd, J=
5.6Hz, 16.4Hz, 1H), 3.70 (dd, J=8.0Hz, 16.8Hz, 1H), 4.45-4.55 (m, 1H),
6.37 (br s, 1H), 7.13 (d, J=8.0Hz, 1H), 7.26 (d, J=6.8Hz, 1H), 7.47 (t, J
=7.6Hz, 1H)；
13C NMR(100MHz,CDCl3):δ22.5,23.3,35.0,57.0,124.3,127.2,
129.8132.5,139.4,152.2,171.1,204.3.
Carry out HPLC survey timing condition as follows.Use the DAICEL that Daicel company of Japan produces
Chiralpak IE chiral chromatographic column, flowing is normal hexane/isopropanol (volume ratio)=80/20 mutually,
Flow rate of mobile phase is 1.0mL/min, and detection wavelength is 254nm, tmajor=24.9min, tminor=
21.0min.The ee value being configured as S, 2e of product 2e is 99%.
Embodiment 18
Preparation embodiment
In the two-mouth bottle of 500mL, add aluminum trichloride (anhydrous) (AlCl3) 12mmol, then
Adding 60mml tetrachloroethylene solvent, mixture stirs 1 hour at normal temperatures, then in stirring
Under, it is slow added into dissolved with 4-(4-ethylphenyl) methylene-2-methyl-5 (4H)-oxazolone 36
The tetrachloroethylene solution 60mL of mmol, after adding all of tetrachloroethylene solution, heating is anti-
Answering solution, at 100 DEG C, stirring reaction 1 hour, then returns back to room temperature and stirs 2 hours.
After reaction terminates, add the 1mol/L dilute hydrochloric acid solution of 120mL, stir 10 minutes, extraction
Going out organic layer, wash twice aqueous phase with dichloromethane, merge organic facies, rotation is evaporated off solvent, residual
Excess can obtain clean product 1f through column chromatography for separation.Product 1f is again through dichloromethane and petroleum ether weight
Hydrogenation it is directly used in after crystallization.
The determination data of 1f is as follows.
1H NMR(400MHz,CDCl3) δ: 1.19 (t, J=8.0Hz, 3H), 2.17 (s, 3H),
2.54 (q, J=8.0Hz, 2H), 6.82 (d, J=7.2Hz, 1H), 7.04-7.08 (m, 1H), 7.17
(s,1H),7.44(s,1H),7.49(br s,1H)；
13C NMR(100MHz,CDCl3)δ:15.4,24.0,28.7,122.1,123.5,124.9,
127.8,131.6,134.2,143.7,144.2,168.9,194.0.
Embodiment 19
Preparation embodiment
The reaction tube of 300mL is separately added into 1.5mg [Rh ((S)-
TCFP)(cod)]SbF6Catalyst, the substrate 1f [substrate: catalyst=10000:1 (rubs of 6.4g
That ratio)], reaction tube is placed in hydriding reactor, evacuation changes hydrogen three times, at hydrogen shield
The methanol of lower addition 12mL degassing, is finally adjusted to 3bar by Hydrogen Vapor Pressure, at 30 DEG C acutely
Stir 1 hour, stopped reaction, concentrate solvent evaporated, obtain white solid product 2f, product 2f
Productivity be 99%.
The determination data of 2f is as follows.
1H NMR(400MHz,CDCl3): δ 1.23 (t, J=7.6Hz, 3H), 2.06 (s, 3H),
2.68 (q, J=7.6Hz, 2H), 2.89 (dd, J=5.2Hz, 16.8Hz, 1H), 3.70 (dd, J=
8.0Hz, 16.4Hz, 1H), 4.51-4.56 (m, 1H), 6.38 (br s, 1H), 7.34 (d, J=7.6
Hz,1H),7.44-7.48(m,1H),7.56(s,1H)；13NMR(100MHz,CDCl3):δ
15.7,23.2,28.7,34.8,57.0,123.0,126.7,135.0,136.3,144.5,149.3,171.1,
203.9.
Carry out HPLC survey timing condition as follows.Use the DAICEL that Daicel company of Japan produces
Chiralpak IE chiral chromatographic column, flowing is normal hexane/isopropanol (volume ratio)=80/20 mutually,
Flow rate of mobile phase is 1.0mL/min, and detection wavelength is 254nm, tmajor=23.0min, tminor=
19.7min.The ee value being configured as S, 2f of product 2f is 99%.
Embodiment 20
Preparation embodiment
In the two-mouth bottle of 500mL, add aluminum trichloride (anhydrous) (AlCl3) 12mmol, then
Adding 60mml tetrachloroethylene solvent, mixture stirs 1 hour at normal temperatures, then in stirring
Under, it is slow added into dissolved with 4-(4-phenyl) methylene-2-methyl-5 (4H)-oxazolone 36
The tetrachloroethylene solution 60mL of mmol, after adding all of tetrachloroethylene solution, heating is anti-
Answering solution, at 100 DEG C, stirring reaction 1 hour, then returns back to room temperature and stirs 2 hours.
After reaction terminates, add the 1mol/L dilute hydrochloric acid solution of 120mL, stir 10 minutes, extraction
Going out organic layer, wash twice aqueous phase with dichloromethane, merge organic facies, rotation is evaporated off solvent, residual
Excess can obtain clean product 1g through column chromatography for separation.Product 1g is again through dichloromethane and petroleum ether weight
Hydrogenation it is directly used in after crystallization.
The determination data of 1g is as follows.
1H NMR(400MHz,CDCl3) δ: 2.20 (s, 3H), 6.99 (d, J=8.0Hz, 1H),
7.32-7.36(m,1H),7.39-7.45(m,2H),7.47-7.50(m,1H),7.50-7.54(m,3H)
7.55-7.58(m,2H)；
13C NMR(100MHz,CDCl3)δ:24.1,122.5,122.6,124.5,126.6,
127.9,128.2,129.1,132.1,133.6,140.0,140.5,145.7,168.7,193.4.
Embodiment 21
Preparation embodiment
The reaction tube of 300mL is separately added into 1.5mg [Rh ((S, S)-
Miniphos)(cod)]SbF6Catalyst, the substrate 1g of 15.8g [substrate: catalyst=20000:
1 (mol ratio)], reaction tube is placed in hydriding reactor, evacuation changes hydrogen three times, at hydrogen
The lower oxolane adding 30mL degassing of protection, is finally adjusted to 8bar, at 25 DEG C by Hydrogen Vapor Pressure
Under be stirred vigorously 9 hours, stopped reaction, concentrate solvent evaporated, obtain white solid product 2g,
The productivity of product 2g is 99%.
The determination data of 2g is as follows.
1H NMR(400MHz,CDCl3): δ 2.09 (s, 3H), 3.00 (dd, J=5.2Hz, 16.8
Hz, 1H), 3.77 (dd, J=8.0Hz, 16.8Hz, 1H), 4.54-4.61 (m, 1H), 6.36 (br s,
1H), 7.37 (t, J=7.2Hz, 1H), 7.42-7.47 (m, 2H), 7.50 (d, J=8.0Hz, 1H),
7.55-7.59(m,2H),7.83-7.87(m,1H),7.96(s,1H)；
13C NMR(100MHz,CDCl3):δ23.2,34.8,57.1,122.5,127.2,127.3,
128.1,129.2,135.0,135.4,139.9,141.5,150.5,171.0,203.6.
Carry out HPLC survey timing condition as follows.Use the DAICEL that Daicel company of Japan produces
Chiralpak IA chiral chromatographic column, flowing is normal hexane/isopropanol (volume ratio)=80/20 mutually,
Flow rate of mobile phase is 1.0mL/min, and detection wavelength is 254nm, tmajor=14.4min, tminor=
22.0min.The ee value being configured as S, 2g of product 2g is 99%.
Embodiment 22
Preparation embodiment
In the two-mouth bottle of 500mL, add aluminum trichloride (anhydrous) (AlCl3) 12mmol, then
Adding 60mml tetrachloroethylene solvent, mixture stirs 1 hour at normal temperatures, then in stirring
Under, it is slow added into dissolved with 4-(4-methoxycarbonyl group phenyl) methylene-2-methyl-5 (4H)-oxazole
The tetrachloroethylene solution 60mL of ketone 36mmol, after adding all of tetrachloroethylene solution,
Reacting by heating solution, at 100 DEG C, stirring reaction 1 hour, then returns back to room temperature and stirs 2
Hour.After reaction terminates, add the 1mol/L dilute hydrochloric acid solution of 120mL, stir 10 minutes,
Extracting organic layer, wash twice aqueous phase with dichloromethane, merge organic facies, rotation is evaporated off solvent,
Residue can obtain clean product 1h through column chromatography for separation.Product 1h is again through dichloromethane and petroleum ether
Hydrogenation it is directly used in after recrystallization.
The determination data of 1h is as follows.
1H NMR(400MHz,CDCl3) δ: 2.20 (s, 3H), 3.89 (s, 3H), 7.01 (d, J=
7.6Hz, 1H), 7.51 (s, 1H), 7.57 (br s, 1H), 7.94 (s, 1H), 8.02 (d, J=7.6Hz,
1H)；
13C NMR(100MHz,DMSO-d6)δ:23.9,52.8,122.3,122.9,123.1,
127.5,128.6,135.8,137.6,152.5,165.9,170.5,192.4.
Embodiment 23:
Preparation embodiment
The reaction tube of 300mL is separately added into 1.5mg [Rh ((S, S)-
Miniphos)(cod)]SbF6Catalyst, the substrate 1h of 14.7g [substrate: catalyst=20000:
1 (mol ratio)], reaction tube is placed in hydriding reactor, evacuation changes hydrogen three times, at hydrogen
The lower ethanol adding 30mL degassing of protection, is finally adjusted to 6bar, at 25 DEG C by Hydrogen Vapor Pressure
It is stirred vigorously 15 hours, stopped reaction, concentrates solvent evaporated, obtain white solid product 2h, produce
The productivity of thing 2h is 99%.
The determination data of 2h is as follows.
1H NMR(400MHz,CDCl3) δ: 2.07 (s, 3H), 3.04 (dd, J=5.6Hz,
17.6Hz,1H),3.73-3.82(m,1H),3.93(s,3H),4.51-4.57(m,1H),6.34(br s,
1H), 7.53 (d, J=8.0Hz, 1H), 8.26-8.31 (m, 1H), 8.39 (s, 1H)；
13C NMR(100MHz,CDCl3)δ:23.1,35.0,52.7,57.0,125.9,127.1,
130.5,135.2,136.5,155.9,166.2,171.0,202.7.
Carry out HPLC survey timing condition as follows.Use the DAICEL that Daicel company of Japan produces
Chiralpak IA chiral chromatographic column, flowing is normal hexane/isopropanol (volume ratio)=80/20 mutually,
Flow rate of mobile phase is 1.0mL/min, and detection wavelength is 254nm, tmajor=14.9min, tminor=
18.7min.The ee value being configured as S, 2h of product 2h is 99%.
Embodiment 24:
Preparation embodiment
In the two-mouth bottle of 500mL, add aluminum trichloride (anhydrous) (AlCl3) 12mmol, then
Adding 60mml tetrachloroethylene solvent, mixture stirs 1 hour at normal temperatures, then in stirring
Under, it is slow added into dissolved with 4-(4-fluorophenyl) methylene-2-methyl-5 (4H)-oxazolone 36mmol
Tetrachloroethylene solution 60mL, after adding all of tetrachloroethylene solution, reacting by heating is molten
Liquid, at 100 DEG C, stirring reaction 1 hour, then returns back to room temperature and stirs 2 hours.Reaction
After end, add the 1mol/L dilute hydrochloric acid solution of 120mL, stir 10 minutes, extracted
Machine layer, washes twice aqueous phase with dichloromethane, merges organic facies, and rotation is evaporated off solvent, residue
Clean product can be obtained through column chromatography for separation.Product is straight after dichloromethane and petroleum ether recrystallization again
Connect for hydrogenation.
The determination data of 1i is as follows.
1H NMR(400MHz,CDCl3)δ:2.18(s,3H),6.86-6.89(m,1H),
6.90-6.96(m,1H),7.02-7.06(m,1H),7.47(s,1H),7.48(br s,1H)；
13C NMR(100MHz,CDCl3)δ:24.0,112.3,112.6,120.3,120.5,
122.9,123.0,124.6,129.4,132.1,142.2,161.3,163.7,168.6,192.3.
Embodiment 25:
Preparation embodiment
The reaction tube of 300mL is separately added into 1.5mg [Rh ((S)-
TCFP)(cod)]SbF6Catalyst, the substrate 1i [substrate: catalyst=10000:1 (rubs of 6.2g
That ratio)], reaction tube is placed in hydriding reactor, evacuation changes hydrogen three times, at hydrogen shield
The ethanol of lower addition 12mL degassing, is finally adjusted to 12bar by Hydrogen Vapor Pressure, acute at 30 DEG C
Strong stirring 2 hours, stopped reaction, concentrate solvent evaporated, obtain white solid product 2i, product
The productivity of 2i is 99%.
The determination data of 2i is as follows.
1H NMR(400MHz,CDCl3): δ 2.09 (s, 3H), 2.97 (dd, J=5.2Hz, 16.4
Hz, 1H), 3.71 (dd, J=8.0Hz, 16.4Hz, 1H), 4.52-4.58 (m, 1H), 6.31 (br s,
1H),7.33-7.39(m,1H),7.40-7.47(m,1H)；
13C NMR(100MHz,CDCl3):δ23.1,34.3,57.4,110.2,110.4,123.5,
123.7,128.4,128.5,147.0,161.4,163.8,171.0,202.6.
Carry out HPLC survey timing condition as follows.Use the DAICEL that Daicel company of Japan produces
Chiralpak IE chiral chromatographic column, flowing is normal hexane/isopropanol (volume ratio)=80/20 mutually,
Flow rate of mobile phase is 1.0mL/min, and detection wavelength is 254nm, tmajor=18.1min, tminor=
16.6min.The ee value being configured as S, 2i of product 2i is 99%.
Embodiment 26:
Preparation embodiment
In the two-mouth bottle of 500mL, add aluminum trichloride (anhydrous) (AlCl3) 12mmol, then
Adding 60mml tetrachloroethylene solvent, mixture stirs 1 hour at normal temperatures, then in stirring
Under, it is slow added into dissolved with 4-(4-chlorphenyl) methylene-2-methyl-5 (4H)-oxazolone 36mmol
Tetrachloroethylene solution 60mL, after adding all of tetrachloroethylene solution, reacting by heating is molten
Liquid, at 100 DEG C, stirring reaction 1 hour, then returns back to room temperature and stirs 2 hours.Reaction
After end, add the 1mol/L dilute hydrochloric acid solution of 120mL, stir 10 minutes, extracted
Machine layer, washes twice aqueous phase with dichloromethane, merges organic facies, and rotation is evaporated off solvent, residue
Clean product 1j can be obtained through column chromatography for separation.Product 1j is again through dichloromethane and petroleum ether recrystallization
After be directly used in hydrogenation.
The determination data of 1j is as follows.
1H NMR(400MHz,CDCl3) δ: 2.19 (s, 3H), 6.87 (d, J=7.6Hz, 1H),
7.24 (dd, J=2.0Hz, 7.6Hz, 1H), 7.26-7.28 (m, 1H), 7.48 (s, 1H), 7.52 (br
s,1H)；
13C NMR(100MHz,DMSO-d6)δ:23.9,123.5,123.7,124.1,129.2,
131.8,133.9,134.9,145.8,170.3,192.5.
Embodiment 27:
Preparation embodiment
The reaction tube of 300mL is separately added into 1.5mg [Rh ((S, S)-
Miniphos)(cod)]SbF6Catalyst, the substrate 1j of 13.2g [substrate: catalyst=20000:
1 (mol ratio)], reaction tube is placed in hydriding reactor, evacuation changes hydrogen three times, at hydrogen
The lower oxolane adding 30mL degassing of protection, is finally adjusted to 16bar by Hydrogen Vapor Pressure,
It is stirred vigorously at 25 DEG C 10 hours, stopped reaction, concentrates solvent evaporated, obtain white solid product
2j, the productivity of product 2j is 99%.
The determination data of 2j is as follows.
1H NMR(400MHz,CDCl3): δ 2.08 (s, 3H), 2.96 (dd, J=5.2Hz, 16.8
Hz, 1H), 3.71 (dd, J=8.4Hz, 16.8Hz, 1H), 4.48-4.54 (m, 1H), 6.22 (br s,
1H), 7.40 (d, J=8.4Hz, 1H), 7.59 (dd, J=2.0Hz, 8.4Hz, 1H), 7.73 (d, J
=2.0Hz, 1H)；
13C NMR(100MHz,CDCl3):δ23.1,34.5,57.1,124.2,128.2,134.4,
135.9,135.9,136.3,149.6,170.9,202.2.
Carry out HPLC survey timing condition as follows.Use the DAICEL that Daicel company of Japan produces
Chiralpak IE chiral chromatographic column, flowing is normal hexane/isopropanol (volume ratio)=80/20 mutually,
Flow rate of mobile phase is 1.0mL/min, and detection wavelength is 254nm, tmajor=20.1min, tminor=
18.4min.The ee value being configured as S, 2j of product 2j is 99%.
Embodiment 28:
Preparation embodiment
In the two-mouth bottle of 500mL, add aluminum trichloride (anhydrous) (AlCl3) 12mmol, then
Adding 60mml tetrachloroethylene solvent, mixture stirs 1 hour at normal temperatures, then in stirring
Under, it is slow added into dissolved with 4-(4-bromophenyl) methylene-2-methyl-5 (4H)-oxazolone 36mmol
Tetrachloroethylene solution 60mL, after adding all of tetrachloroethylene solution, reacting by heating is molten
Liquid, at 100 DEG C, stirring reaction 1 hour, then returns back to room temperature and stirs 2 hours.Reaction
After end, add the 1mol/L dilute hydrochloric acid solution of 120mL, stir 10 minutes, extracted
Machine layer, washes twice aqueous phase with dichloromethane, merges organic facies, and rotation is evaporated off solvent, residue
Clean product 1k can be obtained through column chromatography for separation.Product 1k is again through dichloromethane and petroleum ether recrystallization
After be directly used in hydrogenation.
The determination data of 1k is as follows.
1H NMR(400MHz,CDCl3) δ: 2.19 (s, 3H), 6.82 (d, J=8.4Hz, 1H),
7.35-7.50(m,4H)；
13C NMR(100MHz,DMSO-d6)δ:23.9,119.8,124.1,124.2,126.1,
129.3,133.7,137.9,146.2,170.3,192.5.
Embodiment 29:
Preparation embodiment
The reaction tube of 300mL is separately added into 1.5mg [Rh ((S, S)-
Miniphos)(cod)]SbF6Catalyst, the substrate 1k of 16.0g [substrate: catalyst=20000:
1 (mol ratio)], reaction tube is placed in hydriding reactor, evacuation changes hydrogen three times, at hydrogen
The lower ethanol adding 30mL degassing of protection, is finally adjusted to 18bar, at 25 DEG C by Hydrogen Vapor Pressure
Under be stirred vigorously 22 hours, stopped reaction, concentrate solvent evaporated, obtain white solid product 2k,
The productivity of product 2k is 99%.
The determination data of 2k is as follows.
1H NMR(400MHz,CDCl3): δ 2.09 (s, 3H), 2.96 (dd, J=5.2Hz, 16.8
Hz, 1H), 3.69 (dd, J=8.0Hz, 16.8Hz, 1H), 4.49-4.55 (m, 1H), 6.38 (br s,
1H), 7.36 (d, J=8.4Hz, 1H), 7.75 (dd, J=1.6Hz, 8.4Hz, 1H), 7.89 (d, J
=1.6Hz, 1H)；
13C NMR(100MHz,CDCl3):δ23.1,34.4,57.0,122.2,127.3,128.5,
136.6,138.6,150.1,171.1,202.2.
Carry out HPLC survey timing condition as follows.Use the DAICEL that Daicel company of Japan produces
Chiralpak IE chiral chromatographic column, flowing is normal hexane/isopropanol (volume ratio)=80/20 mutually,
Flow rate of mobile phase is 1.0mL/min, and detection wavelength is 254nm, tmajor=20.4min, tminor=
19.0min.The ee value being configured as S, 2k of product 2k is 99%.
Embodiment 30:
Preparation embodiment
In the two-mouth bottle of 500mL, add aluminum trichloride (anhydrous) (AlCl3) 12mmol, then
Adding 60mml tetrachloroethylene solvent, mixture stirs 1 hour at normal temperatures, then in stirring
Under, it is slow added into dissolved with 4-(2-naphthyl) methylene-2-methyl-5 (4H)-oxazolone 36mmol
Tetrachloroethylene solution 60mL, after adding all of tetrachloroethylene solution, reacting by heating is molten
Liquid, at 100 DEG C, stirring reaction 1 hour, then returns back to room temperature and stirs 2 hours.Reaction
After end, add the 1mol/L dilute hydrochloric acid solution of 120mL, stir 10 minutes, extracted
Machine layer, washes twice aqueous phase with dichloromethane, merges organic facies, and rotation is evaporated off solvent, residue
Clean product 1l can be obtained through column chromatography for separation.Product 1l is again through dichloromethane and petroleum ether recrystallization
After be directly used in hydrogenation.
The determination data of 1l is as follows.
1H NMR(400MHz,CDCl3) δ: 2.21 (s, 3H), 7.21 (s, 1H), 7.37 (t, J=
7.2Hz, 1H), 7.48 (t, J=7.2Hz, 1H), 7.61 (br s, 1H), 7.64 (d, J=8.0Hz,
1H), 7.73 (d, J=7.2Hz, 1H), 7.74 (s, 1H), 7.79 (s, 1H)；
13C NMR(100MHz,CDCl3)δ:24.2,121.0,125.6,126.6,126.8,
128.8,129.7,131.3,132.9,135.3,137.5,140.3,168.6,191.5.
Embodiment 31:
Preparation embodiment
The reaction tube of 300mL is separately added into 1.5mg [Rh ((S, S)-
Miniphos)(cod)]SbF6Catalyst, the substrate 1l [substrate: catalyst=10000:1 of 7.1g
(mol ratio)], reaction tube is placed in hydriding reactor, evacuation changes hydrogen three times, at hydrogen
The lower oxolane adding 30mL degassing of protection, is finally adjusted to 6bar, at 25 DEG C by Hydrogen Vapor Pressure
Under be stirred vigorously 5 hours, stopped reaction, concentrate solvent evaporated, obtain white solid product 2l,
The productivity of product 2l is 99%.
The determination data of 2l is as follows.
1H NMR(400MHz,CDCl3):δ2.11(s,3H),2.06-3.13(m,1H),3.95
(dd, J=8.4Hz, 16.4Hz, 1H), 4.63-4.70 (m, 1H), 6.32 (br s, 1H), 7.48-7.54
(m, 1H), 7.58-7.63 (m, 1H), 7.83-7.87 (m, 2H), 7.97 (d, J=8.4Hz, 1H),
8.33(s,1H)；
13C NMR(100MHz,CDCl3):δ23.3,34.8,57.5,125.2,125.5,126.7,
128.1,129.3,130.7,132.4,132.7,137.9,143.9,171.0,203.8.
Carry out HPLC survey timing condition as follows.Use the DAICEL that Daicel company of Japan produces
Chiralpak IE chiral chromatographic column, flowing is normal hexane/isopropanol (volume ratio)=80/20 mutually,
Flow rate of mobile phase is 1.0mL/min, and detection wavelength is 254nm, tmajor=41.3min, tminor=
35.8min.The ee value being configured as S, 2l of product 2l is 99%.
Embodiment 32:
Preparation embodiment
In the two-mouth bottle of 500mL, add aluminum trichloride (anhydrous) (AlCl3) 12mmol, then
Adding 60mml tetrachloroethylene solvent, mixture stirs 1 hour at normal temperatures, then in stirring
Under, it is slow added into dissolved with 4-(2,3-Dichlorobenzene base) methylene-2-methyl-5 (4H)-oxazolone
The tetrachloroethylene solution 60mL of 36mmol, after adding all of tetrachloroethylene solution, heating
Reaction solution, at 100 DEG C, stirring reaction 1 hour, then returns back to room temperature and stirs 2 hours.
After reaction terminates, add the 1mol/L dilute hydrochloric acid solution of 120mL, stir 10 minutes, extraction
Going out organic layer, wash twice aqueous phase with dichloromethane, merge organic facies, rotation is evaporated off solvent, residual
Excess can obtain clean product 1m through column chromatography for separation.Product 1m is again through dichloromethane and petroleum ether
Hydrogenation it is directly used in after recrystallization.
The determination data of 1m is as follows.
1H NMR(400MHz,CDCl3)δ:2.21(s,3H),7.16(s,2H),7.51(br s,
1H),7.61(s,1H)；
13C NMR(100MHz,DMSO-d6)δ:24.0,119.6,122.9,124.6,127.2,
129.2,135.5,138.6,147.1,170.8,191.6.
Embodiment 33:
Preparation embodiment
The reaction tube of 300mL is separately added into 1.5mg [Rh ((S, S)-
Miniphos)(cod)]SbF6Catalyst, the substrate 1m of 7.1g [substrate: catalyst=10000:
1 (mol ratio)], reaction tube is placed in hydriding reactor, evacuation changes hydrogen three times, at hydrogen
The lower oxolane adding 30mL degassing of protection, is finally adjusted to 6bar, at 25 DEG C by Hydrogen Vapor Pressure
Under be stirred vigorously 5 hours, stopped reaction, concentrate solvent evaporated, obtain white solid product 2l,
The productivity of product 2m is 99%.
The determination data of 2m is as follows.
1H NMR(400MHz,CDCl3): δ 2.08 (s, 3H), 3.01 (dd, J=4.8Hz, 17.2
Hz, 1H), 3.74 (dd, J=8.0Hz, 17.2Hz, 1H), 4.40-4.46 (m, 1H), 6.17 (br s,
1H), 7.52 (d, J=8.0Hz, 1H), 7.62 (d, J=8.0Hz, 1H)；
13C NMR(100MHz,CDCl3)δ:23.0,34.2,56.8,123.0,130.7,135.0,
140.3,151.1,170.8,201.5.
Carry out HPLC survey timing condition as follows.Use the DAICEL that Daicel company of Japan produces
Chiralpak IE chiral chromatographic column, flowing is normal hexane/isopropanol (volume ratio)=80/20 mutually,
Flow rate of mobile phase is 1.0mL/min, and detection wavelength is 254nm, tmajor=16.2min, tminor=
14.4min.The ee value being configured as S, 2m of product 2m is 99%.
Application examples 1
0.95g compound 2a is dissolved in the anhydrous tetrahydro furan of 50mL, reaction is cooled down
To-78 DEG C, it is slowly added dropwise the 1M borine tetrahydrofuran solution of 8mL at such a temperature, dropping
After-78 DEG C react 3 hours.TLC detection reaction completely, is slowly added dropwise at-78 DEG C
3mL methanol cancellation is reacted.After reaction being warmed to room temperature, rotary evaporation obtains thick product, uses two
Chloromethanes extracts with water, merges organic facies, and concentrate drying obtains white solid.Column chromatography obtains 0.81g
White solid 3a, productivity is 86%.
The 0.81g compound 3a obtained is placed in 100mL reaction bulb, adds 30mL 3M
Hydrochloric acid solution, be heated to reflux 8 hours, be cooled to after room temperature add sodium hydroxide regulation pH extremely
Alkalescence, adds dichloromethane extraction, and organic facies is dried and is concentrated to give white solid, and column chromatography obtains 0.47
G compound 4a, productivity is 75%.
The determination data of product 4a is as follows:
1H NMR(400MHz,CDCl3): δ 2.60 (bs, 3H), 2.70 (dd, J=6.2,15.0
Hz, 1H), 3.10 (dd, J=6.2,15.0Hz, 1H), 3.40-3.87 (m, 1H), 4.78 (d, J=5.5
Hz,1H),7.19-7.41(m,4H)；
13C NMR(100MHz,CDCl3):δ41.0,56.7,77.1,127.7,126.9,128.9,
130.4,143.1,145.3.
[α]D 25=+62 (c 0.5, CHCl3).
The amido alcohol of above-mentioned synthesis is widely used in organic synthesis, documents below as part
For reference example (S.Rodr í guez-Escrich, L.Sol à, C.Jimeno, C.Rodr í guez-Escrich,
M.A.Percàs,Adv.Synth.Catal.2008,350,2250-2260.)。
Above the specific embodiment of the present invention is described.It is to be appreciated that the present invention
Being not limited to above-mentioned particular implementation, those skilled in the art can be at the model of claim
Making various deformation or amendment in enclosing, this has no effect on the flesh and blood of the present invention.
Claims (7)
1. ring-type α-dehydrogenation amido ketone, it is the compound represented such as following formula (1),
Wherein, R is selected from hydrogen atom, C1-C6 alkyl, phenyl, substituted-phenyl, C1-C7
Acyl group, C1-C7 alkoxy acyl, hydroxyl, C1-C7 alkoxyl, C1-C7 acyloxy, amino,
Single (C1-C7 alkyl) amido, two (C1-C7 alkyl) amido, C1-C7 amide groups, front three
Base is silica-based, dihydroxy boryl, diphenylphosphine epoxide, phenylmercapto, fluorine atom, chlorine atom,
One or more in bromine atoms, atomic iodine.
2. chiral ring α-amido ketone, it is the compound represented such as following formula (2),
Wherein, R is selected from hydrogen atom, C1-C6 alkyl, phenyl, substituted-phenyl, C1-C7
Acyl group, C1-C7 alkoxy acyl, hydroxyl, C1-C7 alkoxyl, C1-C7 acyloxy, amino,
Single (C1-C7 alkyl) amido, two (C1-C7 alkyl) amido, C1-C7 amide groups, front three
Base is silica-based, dihydroxy boryl, diphenylphosphine epoxide, phenylmercapto, fluorine atom, chlorine atom,
One or more in bromine atoms, atomic iodine,
Be designated as chiral carbon, it is R configuration or S configuration.
3. the preparation method of chiral ring α-amido ketone, it is characterised in that:
In organic solvent, under the catalytic action of double phosphine-rhodium complexs, following formula (1) table
The ring-type α shown-dehydrogenation amido ketone reacts under an atmosphere of hydrogen, obtains following formula (2) table
Chiral ring α-amido the ketone shown,
Wherein, R is selected from hydrogen atom, C1-C6 alkyl, phenyl, substituted-phenyl, C1-C7
Acyl group, C1-C7 alkoxy acyl, hydroxyl, C1-C7 alkoxyl, C1-C7 acyloxy, amino,
Single (C1-C7 alkyl) amido, two (C1-C7 alkyl) amido, C1-C7 amide groups, front three
Base is silica-based, dihydroxy boryl, diphenylphosphine epoxide, phenylmercapto, fluorine atom, chlorine atom,
One or more in bromine atoms, atomic iodine,
In formula (2), the be designated as chiral carbon of *, it is R configuration or S configuration.
The preparation method of chiral ring α-amido ketone the most according to claim 3, its feature
It is:
The described pair of phosphine-rhodium complex is the coordination compound represented by formula [Rh (L) (L ')] X,
Wherein, L is selected from following (R)-BINAP, (R)-Segphos, (R, R)-QuinoxP*、
(R,R)-Duphos、(S,S)-BenzP*, (R, R)-Miniphos, (S)-TCFP and theirs is right
Reflect any one chiral diphosphine ligand in isomer:
L ' is for joining selected from pungent two any one auxiliary dienes dilute or 2,5-norbornadiene of 1,5-ring
Body,
X is selected from SbF6 -Or BF4 -Any one anion.
5. according to the preparation method of the chiral ring α-amido ketone described in claim 3 or 4, its
It is characterised by,
Ring-type α-dehydrogenation amido ketone that the described pair of phosphine-rhodium complex and formula (1) represent mole
Ratio is, ring-type α-dehydrogenation amido ketone=1/100 that double phosphines-rhodium complex/formula (1) represents～
1/20000。
6. according to the preparation method of the chiral ring α-amido ketone described in claim 3 or 4, its
It is characterised by,
Described organic solvent is selected from ethyl acetate, dichloromethane, oxolane, methanol, second
In alcohol, isopropanol, trifluoroethanol any one or two or more.
7. according to the preparation method of the chiral ring α-amido ketone described in claim 3 or 4, its
It is characterised by,
Hydrogen Vapor Pressure is 1～100bar, and reaction temperature is 0～50 DEG C, and the response time is 1～48
Hour.
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