CN107417562A - It is catalyzed the method for prochirality alpha ketoamide synthesis of chiral α hydroxy amides - Google Patents
It is catalyzed the method for prochirality alpha ketoamide synthesis of chiral α hydroxy amides Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B41/00—Formation or introduction of functional groups containing oxygen
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- C07D—HETEROCYCLIC COMPOUNDS
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- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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Abstract
The invention provides a kind of brand-new method for preparing chiral alpha hydroxy amide, prepares a series of chiral alpha hydroxyamide compounds to carrying out asymmetric hydrogenation with prochiral alpha ketoamide by using three new tooth aminophosphine ligands, method includes：Under an atmosphere of hydrogen, in the presence of a catalyst, add prochirality alpha ketoamide and alkali carries out asymmetric hydrogenation, obtain chiral alpha hydroxy amide；The catalyst is to be complexed to obtain with chiral ligand by metal iridium salt.Part is readily synthesized used in methods described, reaction with high enantioselectivity, in high yield, high turn over number the characteristics of, most substrates obtain ee values more than more than 99% conversion ratio and 97% 99% in the case of the catalyst amount a ten thousandth, highest turn over number reaches 100000, has high industrial value.
Description
Technical field
The present invention relates to organic and pharmaceutical synthesis chemical field, and in particular to one kind catalysis prochirality alpha-keto amide synthesis hand
The method of property Alpha-hydroxy acid amides.
Background technology
Chiral alpha-hydroxy amide is a kind of bioactivity for being widely present in drug molecule and having potential medical value point
Chemical constitution in son, such as second generation cephalo-type broad-spectrum antibiotic (compound 1 as described below), there is suppressing cell reproduction to live
Property molecule (compound 2 as described below) and brad ykinin antagonists (compound 3 as described below).Other chiral alpha-hydroxyl
Base acid amides can also chemically react to obtain chirality 1,2- amino alcohols by a step, the structure be equally widely present in drug molecule and
In natural products, such as the vasoactive agent phenylephrine (compound 4 as described below) of Hemorrhagic shock, cardiotonic Arbutamine
(Arbutamine, compound 8 as described below) and Denopamine (Denopamine, compound 6 as described below), is controlled
Treat the medicine Mirabegron (compound 7 as described below) of overactive bladder, adrenaline etc..Meanwhile chirality 1,2-
Amino alcohol is also widely used in asymmetric syntheses field as chiral auxiliary and part.
The enormous industrial value being had based on chiral alpha-hydroxy amide in fields such as pharmacy, people are to synthesizing chiral alpha-hydroxyl
The methodology of acid amides conducts in-depth research, and develops a variety of preparation methods, such as chiral resolution racemization Alpha-hydroxy acid amides, utilizes
The passerini reaction of enantioselectivity prepares chiral alpha-hydroxy amide, using α, the asymmetric open loop policy choosing of beta epoxide acid amides
Method for preparing chiral alpha-hydroxy amide and enzymatic of selecting property etc..So far, asymmetric hydrogenation closes as most directly effective
Into chipal compounds method all the time without well solve alpha-keto amide asymmetric hydrogenation.It has been reported that asymmetric hydrogenation
Method, the shortcomings that enantioselectivity is poor, catalytic activity is low, and the substrate scope of application is low always be present.
The content of the invention
To solve the above problems, obtaining the method for chiral alpha-hydroxy amide by alpha-keto amide the invention provides a kind of, urge
Agent dosage can be only ten a ten thousandths (S/C=100000), have huge industrial application value.
The invention provides a kind of method for being catalyzed prochirality alpha-keto amide synthesis of chiral Alpha-hydroxy acid amides, including：
Under an atmosphere of hydrogen, in the presence of a catalyst, add prochirality alpha-keto amide and alkali progress asymmetric hydrogenation is anti-
Should, obtain chiral alpha-hydroxy amide；The catalyst is to be complexed to obtain with chiral ligand by metal iridium salt, and the chiral ligand is
Compound represented by following formula L：
In the formula L, R represents aromatic group, C1-C15Straight or branched alkyl or C3-C15Cyclic saturated hydrocarbon base.
Wherein, when carrying out the asymmetric hydrogenation, reaction temperature is 20-30 DEG C, Hydrogen Vapor Pressure 10-40atm, instead
It it is 5-24 hours between seasonable.
Wherein, when carrying out the asymmetric hydrogenation, reaction temperature is 30 DEG C, and the reaction time is 10-24 hours.
Wherein, the mol ratio of the alkali and the prochirality alpha-keto amide is 1:50-1000.
Wherein, the molar ratio of the prochirality alpha-keto amide and the catalyst is 5000-500000:1.
Wherein, it by the metal iridium salt and the chiral ligand according to mol ratio is 0.5 that the catalyst, which is,:1-1.2 network
Conjunction obtains.
Wherein, the catalyst is made in accordance with the following methods：
The chiral ligand and the metal iridium salt are subjected to complex reaction in isopropanol, obtain the catalyst, instead
The temperature answered is room temperature, and the reaction time is -3 hours 0.5 hour.
Wherein, the catalyst for being complexed to obtain is not isolated, and is directly used in catalysis asymmetry hydrogenation reaction.
Wherein, the metal iridium salt is [Ir (COD) Cl]2。
Wherein, the prochirality alpha-keto amide is the compound that following formula I or II are represented：
In formula in I or II, R1Represent aromatic group, aromatic heterocycle group, C1-C15Side chain alkyl or C3-C15
Cyclic saturated hydrocarbon base, R2、R3C is represented respectively1-C15Straight or branched alkyl, C4-C20Substituted base or unsubstituted
Aromatic group or aromatic heterocycle group or H atom；
In formula II, X expressions-OR4、-NHR4、-NH2、-CN、-NHCOR4、-SO3H、-COOR4、-OCOR4、-CONH2、-
F、-Cl、-Br、-I、-NO2、-OH、-CF3、C1-C15Straight or branched alkyl or C3-C15Cyclic saturated hydrocarbon base, wherein R4
Separately represent C1-C15Straight or branched alkyl or C3-C15Cyclic saturated hydrocarbon base, the substituting group position representated by X
For any one in 1-5 positions or multiple the position of substitution.
The method of catalysis prochirality alpha-keto amide synthesis of chiral Alpha-hydroxy acid amides provided by the invention, simple to operate, cost
It is cheap, while Catalyst Conversion and selectivity are all high, have the characteristics of Atom economy is high, environment-friendly, have high
Industrial value.
Embodiment
As described below is the preferred embodiment of the present invention, it is noted that for those skilled in the art
For, under the premise without departing from the principles of the invention, some improvements and modifications can also be made, these improvements and modifications are also considered as
Protection scope of the present invention.
The invention provides a kind of method for being catalyzed prochirality alpha-keto amide synthesis of chiral Alpha-hydroxy acid amides, including：
Under an atmosphere of hydrogen, in the presence of catalyst (being represented with Ir/f-amphox), add prochirality alpha-keto amide and
Alkali carries out asymmetric hydrogenation, obtains chiral alpha-hydroxy amide；The catalyst Ir/f-amphox is by metal iridium salt and hand
Property part (being represented with f-amphox) complexing obtain, the chiral ligand f-amphox be following formula L represented by compound：
In the formula L, R represents aromatic group, C1-C15Straight or branched alkyl or C3-C15Cyclic saturated hydrocarbon base.
In embodiment of the present invention, the prochirality alpha-keto amide is the compound that following formula I or II are represented：
In formula in I or II, R1Can be the aromatic groups such as phenyl, naphthyl, pyridine, thiophene, furans, quinoline, isoquinoline
The aromatic heterocycle groups such as quinoline, or the big steric hindrance C including the tert-butyl group1-C15Side chain alkyl or C3-C15Cyclic saturated hydrocarbon
Base, R2、R3Can be separately C1-C15Straight or branched alkyl or C4-C20Substituted base or unsubstituted virtue
Perfume base group or aromatic heterocycle group or H atom；
In formula II, X can be-OR4、-NHR4、-NH2、-CN、-NHCOR4、-SO3H、-COOR4、-OCOR4、-
CONH2、-F、-Cl、-Br、-I、-NO2、-OH、-CF3、C1-C15Straight or branched alkyl or C3-C15Cyclic saturated hydrocarbon
Base, wherein R4Separately represent C1-C15Straight or branched alkyl or C3-C15Cyclic saturated hydrocarbon base, taking representated by X
Can be any one or multiple the position of substitution in 1-5 positions for base location.
Specifically, wherein representative prochirality alpha-keto amide includes:
2- (3-hydroxyphenyl)-N-methyl-2-oxoacetamide (2- (3- hydroxy phenyls)-N- methyl -2-
OxoaGetamide)；
N-(tert-butyl)-2-(4-hydroxy-3-(hydroxymethyl)phenyl)-2-oxoacetamide
(the N- tert-butyl groups -2- (4- hydroxyls -3- (methylol) phenyl) -2- oxoaGetamides)；
N-(3,4-dimethoxyphenethyl)-2-(4-hydroxyphenyl)-2-oxoacetamide(N-(3,4-
Dimethoxyphenethyl) -2- (4- hydroxy phenyls) -2- oxos acetyl)；
2- (3,4-bis (benzyloxy) phenyl)-N-methyl-2-oxoacetamide (2- (double (benzyloxies of 3,4-
Base) phenyl)-N- methyl -2- oxoaGetamides)；
N-benzyl-2- (2-chlorophenyl) -2-oxoacetamide (N- benzyls -2- (2- chlorphenyls) -2- oxos
Acetamide)；
2-(3,4-dihydroxyphenyl)-N-(4-(4-hydroxyphenyl)butyl)-2-oxoacetamide
(2- (3,4- hydroxy phenyls)-N- (4- (4- hydroxy phenyls) butyl) -2- oxoaGetamides)；
((3,4- is double by N- benzyls -2- by N-benzyl-2- (3,4-bis (benzyloxy) phenyl) -2-oxoacetamide
(benzyloxy) phenyl) -2- oxoaGetamides)；
N-(4-(3-(2-aminothiazol-4-yl)-2-oxopropyl)phenethyl)-2-oxo-2-
Phenylacetamid e (N- (4- (3- (thiazolamine -4- bases) -2- oxopropyls) phenethyl) -2- oxo -2- phenyl second
Acid amides)；
2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-N-(1-(4-
Methox yphenyl) -2methylpropan-2-yl) -2-oxoacetamide (2- (6- hydroxyl -3- oxygen -3,4- dihydros -
2H- benzos [b] [1,4] oxazine -8- bases)-N- (methyl-propyl -2- bases of 1- (4- methoxyphenyls) -2) -2- oxoaGetamides).
Chemical formula is as follows：
In embodiment of the present invention, the catalyst Ir/f-amphox is by the metal iridium salt and the chiral ligand
F-amphox is 0.5 according to mol ratio:1-1.2 is complexed to obtain.It is preferred that it is 0.5 afterwards:1-0.5:1.1, more preferably 0.5:
1.05.Wherein chiral ligand f-amphox is the symmetrical oxazoline framework counterparts of face chiral ferrocene-of C1, is a kind of new three
Tooth aminophosphine ligand, its structure is as shown in formula L.Alternatively, in the formula, R represents methyl, isopropyl, the tert-butyl group, phenyl
Or benzyl.Alternatively, metal iridium salt is [Ir (COD) Cl]2, its Chinese full name is 1,5- cyclo-octadiene iridium chloride dimers, English
Literary full name is Chloro (1,5-cyclooctadiene) iridium (I) dimer.Alternatively, the catalyst Ir/f-
Amphox is made in accordance with the following methods：
The chiral ligand f-amphox and the metal iridium salt are subjected to complex reaction in isopropanol, obtain described urge
Agent, the temperature of reaction is room temperature, and the reaction time is -3 hours 0.5 hour.Alternatively, the amount of isopropanol does not do particular determination,
It is appropriate.
Alternatively, the catalyst for being complexed to obtain is not isolated, and is directly used in catalysis asymmetry hydrogenation reaction.
In embodiment of the present invention, chiral ligand and the metal iridium isopropanol (iPrOH reaction obtains described urge in)
During agent, reaction temperature can be arranged as required to, but result is shown, temperature is not obvious on complexing result to be influenceed,
So selection is reacted at room temperature.
In embodiment of the present invention, the part used in methods described is easier to synthesize, and catalytic reaction has high mapping
Selectivity, in high yield, high turn over number (TON) the characteristics of, most substrates take in the case of catalyst amount a ten thousandth
More than 99% conversion ratio and more than 97%-99% ee values are obtained, highest turn over number reaches 100000, for the highest reported at present
Value.
In embodiment of the present invention, prochirality alpha-keto amide synthesis of chiral Alpha-hydroxy acid amides is catalyzed by Ir/f-amphox
Method, specifically include：
S01, the chiral ligand and the metal iridium salt existediReacted in PrOH and obtain the catalyst；
S02, under an atmosphere of hydrogen, in the presence of the catalyst, alpha-keto amide class compound and alkali are added, makes such
Asymmetric hydrogenation occurs for compound.
In embodiment of the present invention, the catalyst that S01 is complexed to obtain is not isolated, and is directly used in catalysis asymmetric hydrogenation
Reaction.And continuously carry out S01 and S02.
In embodiment of the present invention, when carrying out the asymmetric hydrogenation, reaction temperature is 20-30 DEG C, Hydrogen Vapor Pressure
For 10-40atm, the reaction time is 5-24 hours.Alternatively, when carrying out the asymmetric hydrogenation, reaction temperature is 30 DEG C,
Reaction time is 10-24 hours.
In embodiment of the present invention, the mol ratio of the alkali and the prochirality alpha-keto amide is 1:50-1000.
In embodiment of the present invention, the molar ratio of the prochirality alpha-keto amide and the catalyst is 5000-
500000:1.Now, there is no any restrictions in practice for alpha-keto amide and the molar ratio of situ catalytic agent, because original position is urged
The height of the catalytic efficiency of agent causes the asymmetric hydrogenation that in the case of using minimal amount of situ catalytic agent, can also make ketone
Successfully carry out, and very high conversion ratio and inducing effect can be obtained.This point can also know from following examples.
In embodiment of the present invention, the molar ratio of the alkali and the chiral ligand is 0.1-4000:1.Alternatively, institute
It is Cs to state alkali2CO3。
In embodiment of the present invention, the mixed system that prochirality alpha-keto amide, alkali and appropriate organic solvent are formed is added
Carry out asymmetric hydrogenation.Alternatively, the organic solvent can be isopropanol.
In embodiment of the present invention, alternatively, the asymmetric hydrogenation formula can be with as follows：
The present invention advantage be mainly reflected in it is following some：(1) three tooth aminophosphine ligand f-amphox synthesis is easy, ferrocene
He oxazolines fragment all only needs 2-3 step reactions can be prepared by, last only to need 1 step reaction two fragments of splicing；(2) part is steady
Fixed, the serial part is insensitive to water and oxygen, convenient to preserve and use；(3) excellent catalytic effect, the System Catalyst is to exhausted
Most of suitable substrates realize 100% conversion and>99% stereoselectivity；(4) Atom economy is high, the catalyst system and catalyzing
Activity is high, most suitable substrates can be obtained with more than 10000 turn over number, highest turn over number is up to 100000.Base
4 points more than, catalyst system and catalyzing of the present invention has wide industrial prospect.It can be successfully used to such as second generation head
Spore class broad-spectrum antibiotic L-Cefamandole, cardiotonic (R)-arbutamine and (R)-denopamine, treat bladder excessive
A series of important drugs such as medicine (R)-mirabegron, adrenaline (R)-Epinephrine and the like of movable disease
Synthesis, for medical industry produce it is significant.
Method provided by the invention is simple to operate, cost is cheap, reaction with high enantioselectivity, in high yield, high conversion
Number (TON), the characteristics of Atom economy is high and environment-friendly, there is high industrial value.
Embodiments of the invention are elaborated below：The present embodiment is carried out lower premised on technical solution of the present invention
Implement, give detailed embodiment and specific operating process, but protection scope of the present invention be clearly not limited to it is following
Embodiment.
In the examples below, what is represented with " mol% " is the material relative to moles the hundred of alpha-keto amide class compound
Divide ratio.
Embodiment 1：N- benzyl -2- hydroxyl -2- phenyl-acetamides (S/ is prepared from N- benzyl -2- carbonyl -2- phenyl-acetamides
C=100000), chemical formula equation is (* represents asymmetric carbon atom in formula)：
Under high-purity argon gas atmosphere, by [Ir (COD) Cl]2(3.4mg, 5.0 × 10-3) and chiral ligand f-amphox mmol
(5.8mg, 10.5 × 10-3Mmol) it is dissolved in isopropanol (10mL), stirs 1 hour at ambient temperature, it is molten obtains orange clarification
Liquid.The 100 orange settled solutions of μ L are taken, after isopropanol to 10 times of volumes, take the orange solution to take 20 μ with micro syringe
L (0.001mol%) orange settled solution, is added to N- benzyl -2- carbonyl -2- phenyl-acetamides (0.2mmol), isopropanol
(1mL) and Cs2CO3In the mixed system of (1mol%).Reaction system is placed in autoclave, in room temperature and H2(40atm) condition
Lower stirring 5 hours.Removal of solvent under reduced pressure, column chromatography for separation (take silicagel column, eluant, eluent：Ethyl acetate), obtain sterling N- benzyls-
2- hydroxyl -2- phenyl-acetamides, product are analyzed through HPLC, measure ee values (99%ee).1HNMR(400MHz,Chloroform-
D) δ 7.46-7.27 (m, 8H), 7.20 (d, J=7.0Hz, 2H), 6.64 (t, J=6.0Hz, 1H), 5.06 (d, J=2.8Hz,
1H), 4.42 (q, J=9.0,7.5Hz, 2H), 3.83 (d, J=3.4Hz, 1H)
Embodiment 2：N- benzyls -2- (2- chlorphenyls) -2- is prepared from N- benzyls -2- (2- chlorphenyls) -2- carbonyls acetamide
Hydroxyl acetamide, chemical formula equation are：
Under high-purity argon gas atmosphere, by [Ir (COD) Cl]2(3.4mg, 5.0 × 10-3) and chiral ligand f-amphox mmol
(5.8mg, 10.5 × 10-3Mmol) it is dissolved in isopropanol (1mL), stirs 1 hour at ambient temperature, it is molten obtains orange clarification
Liquid.The orange solution 20 μ L (0.1mol%) are taken with micro syringe, are added to N- benzyls -2- (2- chlorphenyls) -2- carbonyl second
In the mixed system of acid amides (0.2mmol), isopropanol (1mL) and cesium carbonate (1mol%).Reaction system is placed in autoclave,
In 30 DEG C and H2Stirred 16 hours under the conditions of (10atm).Removal of solvent under reduced pressure, column chromatography for separation (take silicagel column, eluant, eluent：
Ethyl acetate), sterling N- benzyls -2- (2- chlorphenyls) -2- hydroxyl acetamides are obtained, product is analyzed through HPLC, measures ee values
(99.0%ee).1H NMR (400MHz, Chloroform-d) δ 7.48 (dd, J=7.3,2.1Hz, 1H), 7.40 (dd, J=
7.6,1.7Hz, 1H), 7.38-7.23 (m, 5H), 7.23-7.16 (m, 2H), 6.61 (t, J=6.1Hz, 1H), 5.57 (s, 1H),
4.53 (dd, J=15.0,6.0Hz, 1H), 4.44 (dd, J=15.0,5.8Hz, 1H)13C NMR(101MHz,CDCl3)δ
171.59,137.46,137.28,132.65,129.79,128.76,128.61,127.66,127.63,127.47,70.29,
43.79.
Embodiment 3：N- benzyl -2- hydroxyls -2- (o- toluene is prepared from N- benzyl -2- carbonyls -2- (o- tolyls) acetamide
Base) acetamide, chemical formula equation is：
Under high-purity argon gas atmosphere, by [Ir (COD) Cl]2(3.4mg, 5.0 × 10-3) and chiral ligand f-amphox mmol
(5.8mg, 10.5 × 10-3Mmol) it is dissolved in isopropanol (1mL), stirs 1 hour at ambient temperature, it is molten obtains orange clarification
Liquid.The orange solution 20 μ L (0.1mol%) are taken with micro syringe, are added to N- benzyl -2- carbonyls -2- (o- tolyls) second
In the mixed system of acid amides (0.2mmol), isopropanol (1mL) and cesium carbonate (1mol%).Reaction system is placed in autoclave,
In 30 DEG C and H2Stirred 5 hours under the conditions of (40atm).Removal of solvent under reduced pressure, column chromatography for separation (take silicagel column, eluant, eluent：Second
Acetoacetic ester), sterling N- benzyl -2- hydroxyls -2- (o- tolyls) acetamide is obtained, product is analyzed through HPLC, measures ee values (98.8%
ee)。1H NMR (400MHz, Chloroform-d) δ 7.39-7.18 (m, 9H), 6.45 (s, 1H), 5.29 (d, J=2.2Hz,
1H), 4.57-4.41 (m, 2H), 3.50 (d, J=3.1Hz, 1H), 2.42 (s, 3H)13C NMR(101MHz,CDCl3)δ
172.45,137.74,137.20,136.94,131.26,128.80,128.73,127.93,127.66,127.62,126.44,
72.36,43.60,19.32.
Embodiment 4：N- benzyl -2- hydroxyls -2- (m- toluene is prepared from N- benzyl -2- carbonyls -2- (m- tolyls) acetamide
Base) acetamide, chemical formula equation is：
Under high-purity argon gas atmosphere, by [Ir (COD) Cl]2(3.4mg, 5.0 × 10-3) and chiral ligand f-amphox mmol
(5.8mg, 10.5 × 10-3Mmol) it is dissolved in isopropanol (1mL), stirs 1 hour at ambient temperature, it is molten obtains orange clarification
Liquid.The orange solution 20 μ L (0.1mol%) are taken with micro syringe, are added to N- benzyl -2- carbonyls -2- (o- tolyls) second
In the mixed system of acid amides (0.2mmol), isopropanol (1mL) and cesium carbonate (1mol%).Reaction system is placed in autoclave,
In 30 DEG C and H2Stirred 5 hours under the conditions of (40atm).Removal of solvent under reduced pressure, column chromatography for separation (take silicagel column, eluant, eluent：Second
Acetoacetic ester), sterling N- benzyl -2- hydroxyls -2- (o- tolyls) acetamide is obtained, product is analyzed through HPLC, measures ee values (97.0%
ee)。1H NMR (400MHz, Chloroform-d) δ 7.39-7.12 (m, 9H), 6.55 (s, 1H), 5.04 (d, J=3.0Hz,
1H), 4.54-4.38 (m, 2H), 3.70 (d, J=3.4Hz, 1H), 2.37 (s, 3H)13C NMR(101MHz,CDCl3)δ
172.21,139.30,138.71,137.75,129.52,128.81,128.72,127.60,127.54,123.97,74.26,
43.52,21.41.
Embodiment 5：N- benzyls -2- (3- chlorphenyls) -2- is prepared from N- benzyls -2- (3- chlorphenyls) -2- carbonyls acetamide
Hydroxyl acetamide, chemical formula equation are：
Under high-purity argon gas atmosphere, by [Ir (COD) Cl]2(3.4mg, 5.0 × 10-3) and chiral ligand f-amphox mmol
(5.8mg, 10.5 × 10-3Mmol) it is dissolved in isopropanol (1mL), stirs 1 hour at ambient temperature, it is molten obtains orange clarification
Liquid.The orange solution 20 μ L (0.1mol%) are taken with micro syringe, are added to N- benzyls -2- (3- chlorphenyls) -2- carbonyl second
In the mixed system of acid amides (0.2mmol), isopropanol (1mL) and cesium carbonate (1mol%).Reaction system is placed in autoclave,
In 30 DEG C and H2Stirred 5 hours under the conditions of (10atm).Removal of solvent under reduced pressure, column chromatography for separation (take silicagel column, eluant, eluent：Second
Acetoacetic ester), sterling N- benzyls -2- (3- chlorphenyls) -2- hydroxyl acetamides are obtained, product is analyzed through HPLC, measures ee values (97.1%
ee)1H NMR(400MHz,Chloroform-d)δ7.41(s,1H),7.37–7.25(m,6H),7.23–7.16(m,2H),
6.85 (d, J=6.2Hz, 1H), 5.00 (s, 1H), 4.40 (d, J=5.9Hz, 2H), 4.10 (s, 1H)13C NMR(101MHz,
CDCl3)δ171.65,141.36,137.48,134.63,129.99,128.77,128.70,127.69,127.61,126.81,
124.94,73.50,43.45.HRMS m/z:Calcd for[C15H14O2NCl-H]-:274.0640.Found:274.0642.
Embodiment 6：N- benzyls -2- (4- methoxyl groups are prepared from N- benzyls -2- (4- methoxyphenyls) -2- carbonyls acetamide
Phenyl) -2- hydroxyl yl acetamides, chemical formula equation is：
Under high-purity argon gas atmosphere, by [Ir (COD) Cl]2(3.4mg, 5.0 × 10-3) and chiral ligand f-amphox mmol
(5.8mg, 10.5 × 10-3Mmol) it is dissolved in isopropanol (1mL), stirs 1 hour at ambient temperature, it is molten obtains orange clarification
Liquid.The orange solution 20 μ L (0.1mol%) are taken with micro syringe, are added to N- benzyls -2- (4- methoxyphenyls) -2- carbonyls
In the mixed system of yl acetamide (0.2mmol), isopropanol (1mL) and cesium carbonate (1mol%).Reaction system is placed in high pressure
In kettle, in 30 DEG C and H2Stirred 5 hours under the conditions of (10atm).Removal of solvent under reduced pressure, column chromatography for separation (are taken silicagel column, eluted
Agent：Ethyl acetate), sterling N- benzyls -2- (4- methoxyphenyls) -2- hydroxyl acetamides are obtained, product is analyzed through HPLC, measures ee
Value (>99%ee)1H NMR(400MHz,Chloroform-d)δ7.37–7.26(m,6H),7.25–7.18(m,2H),6.95–
6.87(m,2H),6.55(s,1H),5.04(s,1H),4.53–4.38(m,2H),3.82(s,3H),3.64(s,1H).13C NMR
(101MHz,CDCl3)δ172.40,159.91,137.75,131.55,128.73,128.26,127.62,114.31,73.85,
55.34,43.53.
Embodiment 7：N- benzyls -2- (4- fluorophenyls) -2- is prepared from N- benzyls -2- (4- fluorophenyls) -2- carbonyls acetamide
Hydroxyl acetamide, chemical formula equation are：
Under high-purity argon gas atmosphere, by [Ir (COD) Cl]2(3.4mg, 5.0 × 10-3) and chiral ligand f-amphox mmol
(5.8mg, 10.5 × 10-3Mmol) it is dissolved in isopropanol (1mL), stirs 1 hour at ambient temperature, it is molten obtains orange clarification
Liquid.The orange solution 20 μ L (0.1mol%) are taken with micro syringe, are added to N- benzyls -2- (4- fluorophenyls) -2- carbonyl second
In the mixed system of acid amides (0.2mmol), isopropanol (1mL) and cesium carbonate (1mol%).Reaction system is placed in autoclave,
In 30 DEG C and H2Stirred 5 hours under the conditions of (10atm).Removal of solvent under reduced pressure, column chromatography for separation (take silicagel column, eluant, eluent：Second
Acetoacetic ester), obtain sterling N- benzyls -2- (4- fluorophenyls) -2- hydroxyl acetamides, product is analyzed through HPLC, measure ee values (>99%
ee).1H NMR(400MHz,Chloroform-d)δ7.42–7.25(m,5H),7.25–7.15(m,2H),7.09–6.98(m,
2H), 6.81 (t, J=5.8Hz, 1H), 5.03 (s, 1H), 4.48-4.33 (m, 2H), 4.03 (s, 1H)13C NMR(101MHz,
CDCl3)δ172.06,164.02,161.57,137.58,135.31,135.27,128.76,128.57,128.49,127.68,
127.59,115.78,115.57,73.49,43.43.19F NMR(376MHz,CDCl3)δ-113.27.
Embodiment 8：2- (benzos [d] are prepared from 2- (benzo [d] [1,3] dioxy -5- bases)-N- benzyl -2- carbonyls acetamide
[1,3] dioxy -5- bases)-N- benzyl -2- carbonyl acetamides, chemical formula equation is：
Under high-purity argon gas atmosphere, by [Ir (COD) Cl]2(3.4mg, 5.0 × 10-3) and chiral ligand f-amphox mmol
(5.8mg, 10.5 × 10-3Mmol) it is dissolved in isopropanol (1mL), stirs 1 hour at ambient temperature, it is molten obtains orange clarification
Liquid.The orange solution 20 μ L (0.1mol%) are taken with micro syringe, are added to 2- (benzo [d] [1,3] dioxy -5- bases)-N-
In the mixed system of benzyl -2- carbonyls acetamide (0.2mmol), isopropanol (1mL) and cesium carbonate (1mol%).By reaction system
It is placed in autoclave, in 30 DEG C and H2Stirred 5 hours under the conditions of (10atm).Removal of solvent under reduced pressure, column chromatography for separation (take silicon
Glue post, eluant, eluent：Ethyl acetate), sterling 2- (benzo [d] [1,3] dioxy -5- bases)-N- benzyl -2- hydroxyl acetamides are obtained, are produced
Thing is analyzed through HPLC, measures ee values (99.2%ee)1H NMR(400MHz,Chloroform-d)δ7.38–7.25(m,3H),
7.25-7.16 (m, 2H), 6.89-6.82 (m, 2H), 6.77 (d, J=7.8Hz, 1H), 6.70 (t, J=6.0Hz, 1H), 5.95
(q, J=1.5Hz, 2H), 4.95 (d, J=3.0Hz, 1H), 4.50-4.34 (m, 2H), 3.91 (d, J=3.3Hz, 1H)13C
NMR(101MHz,CDCl3)δ172.24,148.09,147.90,137.67,133.33,128.74,127.63,120.72,
108.37,107.10,101.24,73.95,43.49.
Embodiment 9：From N- benzyls -2- (3,4- double (benzyloxy) phenyl) -2- carbonyls acetamide prepare N- benzyls -2- (3,
Double (benzyloxy) phenyl of 4-) -2- hydroxyl acetamides, chemical formula equation is：
Under high-purity argon gas atmosphere, by [Ir (COD) Cl]2(3.4mg, 5.0 × 10-3) and chiral ligand f-amphox mmol
(5.8mg, 10.5 × 10-3Mmol) it is dissolved in isopropanol (1mL), stirs 1 hour at ambient temperature, it is molten obtains orange clarification
Liquid.The orange solution 20 μ L (0.1mol%) are taken with micro syringe, are added to N- benzyls -2- (3,4- double (benzyloxy) benzene
Base) -2- carbonyls acetamide (0.2mmol), isopropanol (1mL) and cesium carbonate (1mol%) mixed system in.By reaction system
It is placed in autoclave, in 30 DEG C and H2Stirred 5 hours under the conditions of (10atm).Removal of solvent under reduced pressure, column chromatography for separation (take silicon
Glue post, eluant, eluent：Ethyl acetate), obtain sterling N- benzyls -2- (3,4- double (benzyloxy) phenyl) -2- hydroxyl acetamides, product warp
HPLC is analyzed, and measures ee values (99.2%ee)1H NMR(400MHz,Chloroform-d)δ7.46–7.39(m,4H),7.38–
7.25 (m, 8H), 7.20-7.12 (m, 2H), 6.98 (s, 1H), 6.89 (d, J=0.8Hz, 2H), 6.45 (t, J=5.9Hz,
1H),5.13(s,2H),5.09(s,2H),4.94(s,1H),4.49–4.30(m,2H),3.69(s,1H).13C NMR
(101MHz,CDCl3)δ172.23,149.28,137.78,137.08,137.00,132.65,128.73,128.51,
128.49,127.88,127.86,127.61,127.59,127.45,127.26,120.25,115.05,113.26,73.86,
71.29,71.23,43.50.
Embodiment 10：N- benzyls -2- (naphthalene -1- bases) -2- hydroxyls are prepared from N- benzyls -2- (naphthalene -1- bases) -2- carbonyls acetamide
Yl acetamide, chemical formula equation are：
Under high-purity argon gas atmosphere, by [Ir (COD) Cl]2(3.4mg, 5.0 × 10-3) and chiral ligand f-amphox mmol
(5.8mg, 10.5 × 10-3Mmol) it is dissolved in isopropanol (1mL), stirs 1 hour at ambient temperature, it is molten obtains orange clarification
Liquid.The orange solution 20 μ L (0.1mol%) are taken with micro syringe, are added to N- benzyls -2- (naphthalene -1- bases) -2- carbonyl acetyl
In the mixed system of amine (0.2mmol), isopropanol (1mL) and cesium carbonate (1mol%).Reaction system is placed in autoclave,
30 DEG C and H2Stirred 5 hours under the conditions of (10atm).Removal of solvent under reduced pressure, column chromatography for separation (take silicagel column, eluant, eluent：Acetic acid
Ethyl ester), obtain sterling N- benzyls -2- (naphthalene -1- bases) -2- hydroxyl acetamides, product is analyzed through HPLC, measure ee values (>99%ee)
.1H NMR(400MHz,Chloroform-d)δ8.17–8.09(m,1H),7.94–7.82(m,2H),7.57–7.47(m,3H),
7.43 (td, J=7.6,7.0,1.3Hz, 1H), 7.31-7.21 (m, 3H), 7.15-7.06 (m, 2H), 6.52-6.35 (m, 1H),
5.59 (s, 1H), 4.41 (qdd, J=15.0,6.0,2.2Hz, 2H), 4.04 (s, 1H)13C NMR(101MHz,CDCl3)δ
172.68,137.60,134.55,134.24,131.08,129.73,128.88,128.63,127.53,127.52,126.94,
126.78,126.09,125.23,123.98,73.11,43.61.
Embodiment 11：N- benzyl -2- hydroxyl -2- (thiophenes are prepared from N- benzyl -2- carbonyls -2- (thiophene -2- bases) acetamide
Fen -2- bases) acetamide, chemical formula equation is：
Under high-purity argon gas atmosphere, by [Ir (COD) Cl]2(3.4mg, 5.0 × 10-3) and chiral ligand f-amphox mmol
(5.8mg, 10.5 × 10-3Mmol) it is dissolved in isopropanol (1mL), stirs 1 hour at ambient temperature, it is molten obtains orange clarification
Liquid.The orange solution 20 μ L (0.1mol%) are taken with micro syringe, are added to N- benzyl -2- carbonyls -2- (thiophene -2- bases) second
In the mixed system of acid amides (0.2mmol), isopropanol (1mL) and cesium carbonate (1mol%).Reaction system is placed in autoclave,
In 30 DEG C and H2Stirred 5 hours under the conditions of (10atm).Removal of solvent under reduced pressure, column chromatography for separation (take silicagel column, eluant, eluent：Second
Acetoacetic ester), sterling N- benzyl -2- hydroxyls -2- (thiophene -2- bases) acetamide is obtained, product is analyzed through HPLC, measures ee values
(99.1%ee)1H NMR (400MHz, Chloroform-d) δ 7.39-7.21 (m, 6H), 7.12 (dt, J=3.5,1.0Hz,
1H), 6.99 (dd, J=5.1,3.5Hz, 1H), 6.73 (s, 1H), 5.36 (d, J=3.6Hz, 1H), 4.55-4.40 (m, 2H),
3.98 (d, J=3.9Hz, 1H)13C NMR(101MHz,CDCl3)δ171.10,142.37,137.51,128.76,127.67,
126.94,126.23,126.13,70.17,43.62.
Embodiment 12：N- methyl -2- hydroxyl -2- phenyl-acetamides are prepared from N- methyl -2- carbonyl -2- phenyl-acetamides,
Chemical formula equation is：
Under high-purity argon gas atmosphere, by [Ir (COD) Cl]2(3.4mg, 5.0 × 10-3) and chiral ligand f-amphox mmol
(5.8mg, 10.5 × 10-3Mmol) it is dissolved in isopropanol (1mL), stirs 1 hour at ambient temperature, it is molten obtains orange clarification
Liquid.The orange solution 20 μ L (0.1mol%) are taken with micro syringe, are added to N- methyl -2- carbonyl -2- phenyl-acetamides
In (0.2mmol), isopropanol (1mL) and cesium carbonate (1mol%) mixed system.Reaction system is placed in autoclave, 30
DEG C and H2Stirred 5 hours under the conditions of (10atm).Removal of solvent under reduced pressure, column chromatography for separation (take silicagel column, eluant, eluent：Acetic acid second
Ester), obtain sterling N- methyl -2- hydroxyl -2- phenyl-acetamides, product is analyzed through HPLC, measure ee values (>99%ee)1H NMR
(400MHz,Chloroform-d)δ7.49–7.31(m,5H),6.27(s,1H),5.01(s,1H),3.87(s,1H),2.82
(d, J=5.0Hz, 3H), 0.09 (s, 1H)13C NMR(101MHz,CDCl3)δ172.81,139.45,128.84,128.62,
126.84,74.15,26.28.HRMS m/z:Calcd for[C9H11O2N+H]+:166.0863.
Embodiment described above only expresses the several embodiments of the present invention, and its description is more specific and detailed, but simultaneously
Therefore the limitation to the scope of the claims of the present invention can not be interpreted as.It should be pointed out that for one of ordinary skill in the art
For, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to the guarantor of the present invention
Protect scope.Therefore, the protection domain of patent of the present invention should be determined by the appended claims.
Claims (10)
- A kind of 1. method for being catalyzed prochirality alpha-keto amide synthesis of chiral Alpha-hydroxy acid amides, it is characterised in that including：Under an atmosphere of hydrogen, in the presence of a catalyst, add prochirality alpha-keto amide and alkali carries out asymmetric hydrogenation, obtain To chiral Alpha-hydroxy acid amides；The catalyst is to be complexed to obtain with chiral ligand by metal iridium salt, and the chiral ligand is following Compound represented by formula L：In the formula L, R represents aromatic group, C1-C15Straight or branched alkyl or C3-C15Cyclic saturated hydrocarbon base.
- 2. the method for catalysis prochirality alpha-keto amide synthesis of chiral Alpha-hydroxy acid amides as claimed in claim 1, it is characterised in that When carrying out the asymmetric hydrogenation, reaction temperature is 20-30 DEG C, Hydrogen Vapor Pressure 10-40atm, reaction time 5-24 Hour.
- 3. the method for catalysis prochirality alpha-keto amide synthesis of chiral Alpha-hydroxy acid amides as claimed in claim 2, it is characterised in that When carrying out the asymmetric hydrogenation, reaction temperature is 30 DEG C, and the reaction time is 10-24 hours.
- 4. the method for catalysis prochirality alpha-keto amide synthesis of chiral Alpha-hydroxy acid amides as claimed in claim 1, it is characterised in that The mol ratio of the alkali and the prochirality alpha-keto amide is 1:50-1000.
- 5. the method for catalysis prochirality alpha-keto amide synthesis of chiral Alpha-hydroxy acid amides as claimed in claim 1, it is characterised in that The molar ratio of the prochirality alpha-keto amide and the catalyst is 5000-500000:1.
- 6. the method for catalysis prochirality alpha-keto amide synthesis of chiral Alpha-hydroxy acid amides as claimed in claim 1, it is characterised in that It by the metal iridium salt and the chiral ligand according to mol ratio is 0.5 that the catalyst, which is,:1-1.2 is complexed to obtain.
- 7. the method for catalysis prochirality alpha-keto amide synthesis of chiral Alpha-hydroxy acid amides as claimed in claim 6, it is characterised in that The catalyst is made in accordance with the following methods：The chiral ligand and the metal iridium salt are subjected to complex reaction in isopropanol, obtain the catalyst, reaction Temperature is room temperature, and the reaction time is -3 hours 0.5 hour.
- 8. the method for the catalysis prochirality alpha-keto amide synthesis of chiral Alpha-hydroxy acid amides as described in claim 1 or 6, its feature exist In the catalyst for being complexed to obtain is not isolated, and is directly used in catalysis asymmetry hydrogenation reaction.
- 9. the method for catalysis prochirality alpha-keto amide synthesis of chiral Alpha-hydroxy acid amides as claimed in claim 1, it is characterised in that The metal iridium salt is [Ir (COD) Cl]2。
- 10. the method for catalysis prochirality alpha-keto amide synthesis of chiral Alpha-hydroxy acid amides, its feature exist as claimed in claim 1 In the prochirality alpha-keto amide is the compound that following formula I or II are represented：In formula in I or II, R1Represent aromatic group, aromatic heterocycle group, C1-C15Side chain alkyl or C3-C15Ring-type Saturated hydrocarbyl, R2、R3Separately represent C1-C15Straight or branched alkyl, C4-C20Substituted base or unsubstituted Aromatic group or aromatic heterocycle group or H atom；In formula II, X expressions-OR4、-NHR4、-NH2、-CN、-NHCOR4、-SO3H、-COOR4、-OCOR4、-CONH2、-F、- Cl、-Br、-I、-NO2、-OH、-CF3、C1-C15Straight or branched alkyl or C3-C15Cyclic saturated hydrocarbon base, wherein R4Point C is not represented independently1-C15Straight or branched alkyl or C3-C15Cyclic saturated hydrocarbon base, the substituting group position representated by X is Any one in 1-5 positions or multiple the position of substitution.
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| CN110452132A (en) * | 2019-07-03 | 2019-11-15 | 台州学院 | A kind of method that selective reduction alpha-keto amide ketone carbonyl prepares Alpha-hydroxy amide |
| CN110734384A (en) * | 2019-09-23 | 2020-01-31 | 南方科技大学 | Preparation method of hydroxyamides |
| CN112390738A (en) * | 2019-08-16 | 2021-02-23 | 凯特立斯（深圳）科技有限公司 | Ezetimibe intermediate compound and synthetic method of ezetimibe |
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| CN108546238A (en) * | 2018-05-23 | 2018-09-18 | 凯特立斯（深圳）科技有限公司 | The asymmetric hydrogenation method of alpha-keto amide class compound |
| CN110452132A (en) * | 2019-07-03 | 2019-11-15 | 台州学院 | A kind of method that selective reduction alpha-keto amide ketone carbonyl prepares Alpha-hydroxy amide |
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| CN112390738A (en) * | 2019-08-16 | 2021-02-23 | 凯特立斯（深圳）科技有限公司 | Ezetimibe intermediate compound and synthetic method of ezetimibe |
| CN112390738B (en) * | 2019-08-16 | 2023-03-31 | 凯特立斯（深圳）科技有限公司 | Ezetimibe intermediate compound and synthetic method of ezetimibe |
| CN110734384A (en) * | 2019-09-23 | 2020-01-31 | 南方科技大学 | Preparation method of hydroxyamides |
| CN110734384B (en) * | 2019-09-23 | 2022-09-20 | 南方科技大学 | Preparation method of hydroxyamide |
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