CN1178517A - Process for reduction of carbonyl compounds - Google Patents
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- CN1178517A CN1178517A CN 97190044 CN97190044A CN1178517A CN 1178517 A CN1178517 A CN 1178517A CN 97190044 CN97190044 CN 97190044 CN 97190044 A CN97190044 A CN 97190044A CN 1178517 A CN1178517 A CN 1178517A
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Abstract
The present invention provides a process for reducing carbonyl compounds to hydroxy compounds, in particular stereoselectively reducing alpha -aminohaloketone derivatives in an easy and simple manner, which comprises reacting a carbonyl compound of the general formula (1) with an organoaluminum compound of the general formula (4) to provide the corresponding alcohol compound of the general formula (5).
Description
Technical field
The present invention relates to a kind of method of reducing carbonyl compound.
Background technology
In various fields, the reduction of carbonyl compound has constituted a crucial technology, for example in the preparation of the intermediate of medicine.Up to now, the hands-on approach of known reducing carbonyl compound can be mentioned Meerwein-Ponndorf-Varley reduction method (MPV reduction method) and use the reduction method of diisobutyl aluminium hydride (DIBAH).
The MPV reduction method is to use tri-alkoxy aluminium such as Al (O-iPr)
3The method of coming reducing carbonyl compound as reductive agent or reducing catalyst.Because used tri-alkoxy aluminium and alcohol are inexpensive as Virahol, thus this method often conduct reduce the method [Organic Reactions (organic reaction), volume 2, the 178 pages (1944)] of economy of various ketone and aldehyde.
Yet the MPV reduction method of this use tri-alkoxy aluminium exists problem.Under low temperature of reaction, reaction is tending towards carrying out very slowly, and this mainly is because mentioned reagent active low.In order to improve speed of reaction and productive rate, need higher temperature of reaction, as be not less than 50 ℃.Therefore, above-mentioned reduction method is not suitable for reducing unsettled carbonyl compound, perhaps shows under the SA situation at carbonyl compound, even this reduction reaction rising temperature of reaction also almost can not be carried out.
In other method, using the method for DIBAH reducing carbonyl compound is industrial ten minutes useful method, because it has good activity and very economic.This method is used for, and for example goes back the alpha-amino group chlorine ketone derivatives that the reason leucine obtains.When under-78 ℃, reducing above-mentioned alpha-amino group chlorine ketone derivatives with DIBAH, can preferentially obtain the erythro product, its diastereomeric excess (diastereomer excess) is about 75%[Tetrahedron Letters (tetrahedron communication), 36,5453 (1995)].
Term used herein " erythro " refers to a kind of isomer, and wherein adjacent amino and hydroxyl show following relative configuration:
Yet this reduction method needs very low temperature to control activity.And when this method was used to reduce above-mentioned alpha-amino group chlorine ketone derivatives, it was high to 90% or more to obtain stereoselectivity (representing with diastereomeric excess).
About reaction with the diisobutyl aluminium hydride reducing carbonyl compound, document points out that the intermediate that diisobutyl aluminum alkoxide (diisobutylaluminum alkoxides) may form reaction partly participates in reduction reaction [Journal of Organic Chemistry (organic chemistry magazine), 38,4232 (1973)].Yet, never have report to point out that dialkyl group one aluminum alkoxide such as diisobutyl aluminum isopropoxide may be effective to the reduction or the Stereoselective reduction of carbonyl compound.Similarly, never having report to point out may be effective to the reduction or the Stereoselective reduction of carbonyl compound as the reductive agent of Virahol preparation with alcohol by dialkyl group aluminum hydride such as diisobutyl aluminium hydride.
In view of the above, an object of the present invention is to provide a kind of method simply and easily that under relatively mild condition, carbonyl compound is reduced into corresponding oxy-compound.Another purpose provides the almost method of reducing of irreducible some carbonyl compound of the common tri-alkoxy aluminium of a kind of usefulness, especially a kind of method of Stereoselective producing alpha-amino ketones derivative.
The general introduction of invention
Main points of the present invention are the reduction at carbonyl compound, and it comprises that the carbonyl compound of general formula (1) and the organo-aluminium compound of general formula (4) react, and obtain the alkylol cpd of corresponding general formula (5).
Wherein, in the general formula (1), if R
1And R
2In one be to replace or unsubstituted alkyl, replacement or unsubstituted aralkyl or replacement or the unsubstituted aryl that contains 6 to 30 carbon atoms, the then R that contains 7 to 30 carbon atoms that contains 1 to 30 carbon atom
1And R
2Expression replaces or unsubstituted alkyl, replacement or unsubstituted aralkyl, replacement or unsubstituted aryl, cyano group, hydrogen atom, the group of general formula (2) or the group of general formula (3) that contains 6 to 30 carbon atoms that contains 7 to 30 carbon atoms that contains 1 to 30 carbon atom separately;
CH
nX
3-n (2)
In the general formula (2), X represents halogen atom, and n represents 0 to 2 integer;
In the general formula (3), Y represents alkoxyl group, aralkoxy, replacement or unsubstituted amino or alkylthio (alkylthio group);
In the general formula (4), R
3And R
4Expression replaces or unsubstituted alkyl, replacement or unsubstituted aralkyl or replacement or the unsubstituted aryl that contains 6 to 20 carbon atoms that contains 7 to 20 carbon atoms that contains 1 to 10 carbon atom R separately
5Expression replaces or unsubstituted primary alkyl, replacement or unsubstituted secondary alkyl, replacement or unsubstituted uncle's aralkyl or replacement or the unsubstituted secondary aralkyl that contains 7 to 30 carbon atoms that contains 7 to 30 carbon atoms that contains 1 to 20 carbon atom that contains 1 to 20 carbon atom;
In the general formula (5), R
1And R
2As above definition.
Brief description of drawings
Fig. 1 is the nmr spectrum (NMR spectrogram) of product [1 (S)-benzyl-2 (S)-hydroxyl-3-chloropropyl] t-butyl carbamate that obtains of embodiment 5.
Fig. 2 is the infrared spectrum (IR spectrogram) of product [1 (S)-benzyl-2 (S)-hydroxyl-3-chloropropyl] t-butyl carbamate that obtains of embodiment 5.
Fig. 3 is the nmr spectrum (NMR spectrogram) of product [1 (S)-benzyl-2 (S)-hydroxyl-3-chloropropyl] Urethylane that obtains of embodiment 8.
Fig. 4 is the infrared spectrum (IR spectrogram) of product [1 (S)-benzyl-2 (S)-hydroxyl-3-chloropropyl] Urethylane that obtains of embodiment 8.
Fig. 5 is the nmr spectrum (NMR spectrogram) of product [1 (R)-thiophenyl methyl-2 (S)-hydroxyl-3-chloropropyl] benzyl carbamate that obtains of embodiment 9.
Fig. 6 is the infrared spectrum (IR spectrogram) of product [1 (R)-thiophenyl methyl-2 (S)-hydroxyl-3-chloropropyl] benzyl carbamate that obtains of embodiment 9.
Fig. 7 be the product 2 that obtains of embodiment 14 (R, S)-nmr spectrum (NMR spectrogram) of hydroxyl-3 (S)-(t-butoxycarbonyl amino)-4-phenylbutyric acid methyl esters.
Fig. 8 be the product 2 that obtains of embodiment 14 (R, S)-infrared spectrum (IR spectrogram) of hydroxyl-3 (S)-(t-butoxycarbonyl amino)-4-phenylbutyric acid methyl esters.
Fig. 9 is the nmr spectrum (NMR spectrogram) of the product that obtains of embodiment 15 [1 (S)-benzyl-2 (R, S)-hydroxyl-3,3-two chloropropyls] urethanum.
Figure 10 is the infrared spectrum (IR spectrogram) of the product that obtains of embodiment 15 [1 (S)-benzyl-2 (R, S)-hydroxyl-3,3-two chloropropyls] urethanum.
The detailed description of invention
About the carbonyls of above general formula (1), if R1And R2In one be to replace or unsubstituted alkyl, replacement or unsubstituted aralkyl or replacement or the unsubstituted aryl that contains 6 to 30 carbon atoms, the then R that contains 7 to 30 carbon atoms that contains 1 to 30 carbon atom1And R2Expression replaces or does not replace separately The alkyl that contains 1 to 30 carbon atom, replacement or the unsubstituted aralkyl that contains 7 to 30 carbon atoms, Replace or the base of the unsubstituted aryl that contains 6 to 30 carbon atoms, cyano group, hydrogen atom, above general formula (2) The group of group or above general formula (3).
As substituting group, can mention halogen atom, alkoxy carbonyl group, alkoxyl, protection amino, cyano group, Nitro, sulfinyl, sulfonyl, alkylthio group etc. R1Or R2Each group of expression all can contain two Individual or how such substituting group.
Above-mentioned replacement or the unsubstituted alkyl that contains 1 to 30 carbon atom are not limited to any specific kind Class, but comprise such as methyl, ethyl, butyl, isopropyl, cyclohexyl etc. Preferably contain 1 to 20 The group of individual carbon atom.
Above-mentioned replacement or the unsubstituted aralkyl that contains 7 to 30 carbon atoms are not limited to any specific Kind, but comprise, for example benzyl, phenylpropyl, phenethyl, to methoxybenzyl, 1-(N-tertbutyloxycarbonyl Amino)-2-phenylethyl, 1-(N-benzyloxycarbonyl amino)-2-phenylethyl etc. Preferably contain 7 to 20 The group of carbon atom.
Above-mentioned replacement or the unsubstituted aryl that contains 6 to 30 carbon atoms are not limited to any specific kind Class, but comprise such as phenyl, rubigan, p-nitrophenyl, naphthyl etc. Preferably contain 6 to 20 The group of individual carbon atom.
About the group of above general formula (2) expression, X represents halogen atom, and n represents 0 to 2 integer.
Above-mentioned halogen atom is not limited to any particular types, but comprises chlorine atom, bromine atoms, iodine atom or fluorine Atom, best chlorine atom.
The group of above-mentioned general formula (2) is not limited to any particular types, but comprises: chloromethyl, dichloromethyl, trichloromethyl, brooethyl, two brooethyls, trisbromomethyl, methyl fluoride, difluoromethyl, trifluoromethyl, iodomethyl, diiodomethyl, three iodomethyls etc.Preferably chloromethyl, dichloromethyl and trichloromethyl.
About the group of above-mentioned general formula (3), Y represents alkoxyl group, aralkoxy, replacement or unsubstituted amino or alkylthio.
Above-mentioned alkoxyl group is not limited to any particular types, but comprises, for example methoxyl group, oxyethyl group, tert.-butoxy etc.The group that preferably contains 1 to 10 carbon atom.
Above-mentioned aralkoxy is not limited to any particular types, but comprises: benzyloxy etc.The group that preferably contains 6 to 20 carbon atoms.
Above-mentioned replacement or unsubstituted amino are not limited to any particular types, but comprise, for example amino, dimethylin etc.
Above-mentioned alkylthio is not limited to any particular types, but comprises: methylthio group, thiophenyl etc.
The group of above-mentioned general formula (3) is not limited to any particular types, but comprises: methoxycarbonyl, ethoxycarbonyl, carbobenzoxy-(Cbz), tertbutyloxycarbonyl etc.Yet, preferably methoxycarbonyl and ethoxycarbonyl.
As the carbonyl compound of above-mentioned general formula (1), for example can mention: aldehyde such as phenyl aldehyde, isobutyric aldehyde etc.; And ketone such as methyl phenyl ketone, Propiophenone, pimelinketone, methyl aceto acetate, methyl benzoylformate, phenacyl chloride, α-dichloroacetophenone, α-Trichloroacetophenon, 4-chloroacetyl acetacetic ester, benzoyl cyanide, 1 (S)-benzyl-2-oxo-3, the 3-dichloro propyl carbamic acid tert-butyl ester, 1 (S)-benzyl-2-oxo-3,3, the 3-trichlorine propyl carbamic acid tert-butyl ester, 3 (S)-(N-benzyloxycarbonyl amino)-2-oxo-4-phenylacetic acid methyl esters etc.
Symbol R about above definition
3And R
4, replacement or the unsubstituted alkyl that contains 1 to 10 carbon atom are not limited to any particular types, but comprise, for example methyl, ethyl, normal-butyl, isobutyl-, sec.-propyl, cyclohexyl, methoxyl methyl etc.Above-mentioned group is preferably and contains 1 to 6 carbon atom, better is isobutyl-.
Still about symbol R
3And R
4, the aralkyl that contains 7 to 20 carbon atoms is not limited to any particular types, but comprises, for example benzyl, 3-phenyl-1-propyl group, α-styroyl, to methoxybenzyl etc.The group that preferably contains 7 to 15 carbon atoms.
Again about symbol R
3And R
4, the aryl that contains 6 to 20 carbon atoms is not limited to any particular types, but comprises, for example phenyl, to hydroxyphenyl, rubigan, p-nitrophenyl, naphthyl etc.The group that preferably contains 6 to 15 carbon atoms.
Symbol R about above definition
5, replace or the unsubstituted primary alkyl that contains 1 to 20 carbon atom or replacement or the unsubstituted secondary alkyl that contains 1 to 20 carbon atom are for example methyl, ethyl, sec.-propyl, cyclohexyl, 2,4-dimethyl-3-amyl group etc.Be preferably the group that contains 1 to 10 carbon atom.Be more preferably sec.-propyl, cyclohexyl and 2,4-dimethyl-3-amyl group.
About symbol R
5, replace or the unsubstituted uncle's aralkyl that contains 7 to 30 carbon atoms or replacement or the unsubstituted secondary aralkyl that contains 7 to 30 carbon atoms are, for example diphenyl-methyl, benzyl, hydrocinnamyl, α-styroyl, to methoxybenzyl etc.Be preferably the group that contains 7 to 15 carbon atoms, be more preferably diphenyl-methyl.
Organo-aluminium compound as above general formula (4) expression, can mention: diisobutyl aluminum isopropoxide, diisobutyl hexichol aluminum methoxide, diisobutyl aluminum ethoxide, diisobutyl cyclohexyloxy aluminium, diisobutyl 2,4-dimethyl-3-pentyloxy aluminium, diethylaluminum ethoxide etc.Wherein, preferably diisobutyl aluminum isopropoxide and diisobutyl hexichol aluminum methoxide.
The organo-aluminium compound of above general formula (4) can be by for example (1) dialkyl group aluminum hydride and alcohol reaction, (2) trialkylaluminium and alcohol reaction (German patent specification No.2507532), (3) use the reaction mixture that obtains as carbonyl compound such as acetone and DIBAH reduction reaction, (4) trialkylaluminium and tri-alkoxy reactive aluminum (German patent specification No.2304617), or (5) trialkylaluminium and trialkyl borate reaction (German patent specification No.2151176) prepares.
The method of reducing carbonyl compound of the present invention can be used for reducing the alpha-amino group ketone derivatives of general formula shown below (6) and the alpha-amino group halogenated derivative of reduction general formula shown below (7).The method of reducing carbonyl compound of the present invention make be prepared as follows from the alpha-amino group ketone derivatives of general formula (6) shown in general formula (8) the α-An Jichun derivative or be prepared as follows from the alpha-amino group halogenated derivative of general formula (7) shown in the alpha-amino group halohydrin derivative of general formula (9) become possibility.α-An Jichun derivative and alpha-amino group halohydrin derivative are useful compounds, as the intermediate of medicinal compound.
The method for preparing above-mentioned α-An Jichun derivative comprises the alpha-amino group ketone derivatives with general formula (6), the particularly organo-aluminium compound of the alpha-amino group halogenated derivative of general formula (7) and above general formula (4) reaction, obtain the α-An Jichun derivative of corresponding general formula (8), particularly the alpha-amino group halohydrin derivative of corresponding general formula (9).Wherein,
In the general formula (6), R
6Expression replaces or unsubstituted alkyl, replacement or unsubstituted aralkyl, replacement or unsubstituted aryl or the hydrogen atom that contains 6 to 20 carbon atoms that contains 7 to 20 carbon atoms that contains 1 to 20 carbon atom, R
7Represent the group of above general formula (2) or the group of above general formula (3), P
1And P
2Represent hydrogen atom or amido protecting group (amino-protecting group) separately, perhaps P
1With P
2Combine expression phthalyl group, but do not comprise P
1And P
2Be the situation of hydrogen atom;
In the general formula (7), X represents halogen atom, R
6As above definition;
In the general formula (8), R
6, R
7, P
1And P
2As above definition;
In the general formula (9), X, R
6, P
1And P
2As above definition.
About the alpha-amino group ketone derivatives of above-mentioned general formula (6) and the alpha-amino group halogenated derivative of general formula (7), R
6It is the side chain of common a-amino acid or by handling the side chain of the alpha-amino acid derivatives that this common a-amino acid obtains, its expression replaces or unsubstituted alkyl, replacement or unsubstituted aralkyl, replacement or unsubstituted aryl or hydrogen atom that contains 6 to 20 carbon atoms that contains 7 to 20 carbon atoms that contains 1 to 20 carbon atom.
Above-mentioned replacement or the unsubstituted alkyl that contains 1 to 20 carbon atom are not limited to any particular types, but comprise, for example methyl, ethyl, sec.-propyl, isobutyl-, the tertiary butyl, methylol, 1-hydroxyethyl, thiopurine methyltransferase, methylthiomethyl etc.The group that preferably contains 1 to 10 carbon atom.
Above-mentioned replacement or the unsubstituted aralkyl that contains 7 to 20 carbon atoms are not limited to any particular types, but comprise, for example benzyl, to acrinyl, to methoxybenzyl, thiophenyl methyl, α-styroyl etc.The group that preferably contains 7 to 15 carbon atoms.
Above-mentioned replacement or the unsubstituted aryl that contains 6 to 20 carbon atoms are not limited to any particular types, but comprise, for example phenyl, to hydroxyphenyl, p-methoxyphenyl etc.The group that preferably contains 6 to 15 carbon atoms.
About the alpha-amino group ketone derivatives of above-mentioned general formula (6) and the alpha-amino group halogenated derivative of above-mentioned general formula (7), P
1And P
2The group of representing hydrogen atom or amido protecting separately, perhaps P
1With P
2Combine expression phthalyl group, but do not comprise P
1And P
2Be the situation of hydrogen atom.
Above-mentioned amido protecting group as long as it can protect amino effectively in the reduction reaction of being discussed, is not limited to any particular types.Therefore, it comprises Protective Groupsin Organic Synthesis (blocking group in the organic synthesis) second edition that Theodora W.Green is shown, John Wiley ﹠amp; Sons; 1990; those blocking groups of recording and narrating in the 309th page to 384 pages, for example: ethoxycarbonyl, methoxycarbonyl, tertbutyloxycarbonyl, carbobenzoxy-(Cbz), ethanoyl, trifluoroacetyl group, benzyl, dibenzyl, tosyl group, benzoyl, phthaloyl etc.Select the amido protecting group preferably to consider the stereoselectivity of reduction reaction.Reduction reaction can be passed through for example to use: carbalkoxy such as methoxycarbonyl, tertbutyloxycarbonyl or ethoxycarbonyl, perhaps aralkoxycarbonyl such as carbobenzoxy-(Cbz) carry out, and very high erythro selectivity (erythroselectivity) is arranged.
About the alpha-amino group ketone derivatives of above-mentioned general formula (6), R
7Represent the group of above general formula (2) or the group of above general formula (3).
About the alpha-amino group halogenated derivative of above-mentioned general formula (7), X represents halogen atom.
Above-mentioned halogen atom is not limited to any particular types, but can be chlorine atom, bromine atoms, iodine atom or fluorine atom.Yet, chlorine atom preferably.The alpha-amino group ketone derivatives of above-mentioned general formula (6) comprises, but be not limited to optically active (S)-(1-benzyl-3-chloro-2-oxopropyl) t-butyl carbamate, (R)-(1-benzyl-3-chloro-2-oxopropyl) t-butyl carbamate, (S)-(1-benzyl-3-chloro-2-oxopropyl) Urethylane, (R)-(1-benzyl-3-chloro-2-oxopropyl) Urethylane, (S)-(1-benzyl-3-chloro-2-oxopropyl) urethanum, (R)-(1-benzyl-3-chloro-2-oxopropyl) urethanum, (S)-(1-thiophenyl methyl-3-chloro-2-oxopropyl) benzyl carbamate, (R)-(1-thiophenyl methyl-3-chloro-2-oxopropyl) benzyl carbamate, (S)-(1-thiophenyl methyl-3-chloro-2-oxopropyl) t-butyl carbamate, (R)-(1-thiophenyl methyl-3-chloro-2-oxopropyl) t-butyl carbamate, (S)-(1-thiophenyl methyl-3-chloro-2-oxopropyl) Urethylane, (R)-(1-thiophenyl methyl-3-chloro-2-oxopropyl) Urethylane, (S)-(t-butoxycarbonyl amino)-2-oxo-4-phenylbutyric acid methyl esters, (R)-(t-butoxycarbonyl amino)-2-oxo-4-phenylbutyric acid methyl esters, (S)-(methoxycarbonyl amino)-2-oxo-4-phenylbutyric acid methyl esters, (R)-(methoxycarbonyl amino)-2-oxo-4-phenylbutyric acid methyl esters, [1 (S)-benzyl-2-oxo-3,3,3-three chloropropyls] benzyl carbamate, [1 (R)-benzyl-2-oxo-3,3,3-three chloropropyls] benzyl carbamate, [1 (S)-benzyl-3,3-two chloro-2-oxopropyls] urethanum, [1 (R)-benzyl-3,3-two chloro-2-oxopropyls] urethanum etc.Above-mentioned alpha-amino group halogenated derivative comprises, but be not limited to optically active (S)-(1-benzyl-3-chloro-2-oxopropyl) t-butyl carbamate, (R)-(1-benzyl-3-chloro-2-oxopropyl) t-butyl carbamate, (S)-(1-benzyl-3-chloro-2-oxopropyl) Urethylane, (R)-(1-benzyl-3-chloro-2-oxopropyl) Urethylane, (S)-(1-benzyl-3-chloro-2-oxopropyl) urethanum, (R)-(1-benzyl-3-chloro-2-oxopropyl) urethanum, (S)-(1-benzyl-3-chloro-2-oxopropyl) benzyl carbamate, (R)-(1-benzyl-3-chloro-2-oxopropyl) benzyl carbamate, (S)-(1-thiophenyl methyl-3-chloro-2-oxopropyl) benzyl carbamate, (R)-(1-thiophenyl methyl-3-chloro-2-oxopropyl) benzyl carbamate
(S)-(1-thiophenyl methyl-3-chloro-2-oxopropyl) t-butyl carbamate,
(R)-(1-thiophenyl methyl-3-chloro-2-oxopropyl) t-butyl carbamate,
(S)-(1-thiophenyl methyl-3-chloro-2-oxopropyl) Urethylane,
(R)-(1-thiophenyl methyl-3-chloro-2-oxopropyl) Urethylane,
(S)-(1-thiophenyl methyl-3-chloro-2-oxopropyl) urethanum,
(R)-(1-thiophenyl methyl-3-chloro-2-oxopropyl) urethanum etc.Wherein, preferably (S)-(1-benzyl-3-chloro-2-oxopropyl) t-butyl carbamate and (S)-(1-thiophenyl methyl-3-chloro-2-oxopropyl) benzyl carbamate.
The method that relates to reducing carbonyl compound of the present invention now, the reduction of the carbonyl compound of general formula (1) is undertaken by following method: the carbonyl compound of general formula (1) is added reaction system or reductive agent added in the carbonyl compound of general formula (1) stirring then.Reduction reaction more fortunately-10 ℃ is carried out to 60 ℃, better carries out at-10 ℃ to 30 ℃.
The consumption of the organo-aluminium compound of general formula (4) better is 1 to 5 molar equivalent, is more preferably 1.5 to 3 molar equivalents, in the carbonyl compound of general formula (1).
The solvent that uses in the present invention's practice is not limited to any particular types, but comprises: molecular formula is R
5The alkylol cpd of OH, wherein R
5With above shown in R in the general formula (4)
5Identical, also have toluene, hexane, hexanaphthene, heptane, tetrahydrofuran (THF), t-butyl methyl ether, 1,2-glycol dimethyl ether, methylene dichloride, N, dinethylformamide etc.(except above-mentioned alcohol), preferably toluene, tetrahydrofuran (THF) and hexane in these solvents.
Though the method for aftertreatment is not limited to any ad hoc approach, but the alkylol cpd product of general formula (5) can be after reacting completely, reclaim by common aftertreatment and separation method, for example by using aqueous acid solution hydrolysis reaction mixture, extractive reaction mixture, concentrate extract, then enriched material is carried out separating treatment with separator column (column), crystallization, distillation and/or other class methods.
The compound of above-mentioned general formula (4) can also prepare by following reaction, and the reaction mixture that so prepares can be used for reducing the carbonyl compound of general formula (1), (6) or (7) at this point.
Therefore, the product that obtains of the alkylol cpd prepared in reaction of the organo-aluminium compound of general formula (10) and general formula (11) can be used to reduce above-mentioned carbonyl compound.
R
5-OH (11)
Wherein, in the general formula (10), R
3And R
4Expression replaces or unsubstituted alkyl, replacement or unsubstituted aralkyl or replacement or the unsubstituted aryl that contains 6 to 20 carbon atoms that contains 7 to 20 carbon atoms that contains 1 to 10 carbon atom separately; In the general formula (11), R
5For replacing or unsubstituted primary alkyl, replacement or unsubstituted secondary alkyl, replacement or unsubstituted uncle's aralkyl or replacement or the unsubstituted secondary aralkyl that contains 7 to 30 carbon atoms that contains 7 to 30 carbon atoms that contains 1 to 20 carbon atom that contains 1 to 20 carbon atom.
The organo-aluminium compound of above general formula (10) is, for example ADEH, diisobutyl aluminium hydride etc.Diisobutyl aluminium hydride preferably wherein.
The alkylol cpd of above general formula (11) has under the strong situation that gives the hydrogen ion ability at it, is not limited to any particular types.For example, can mention Virahol, diphenyl-carbinol, 2,4-dimethyl-3-amylalcohol, hexalin, 2-methoxyl group hexalin etc.Be preferably the alkylol cpd of general formula (12)
(wherein, R
8And R
9Expression replaces or unsubstituted alkyl, replacement or unsubstituted aralkyl or replacement or the unsubstituted aryl that contains 6 to 20 carbon atoms, the perhaps R that contains 7 to 20 carbon atoms that contains 1 to 10 carbon atom separately
8With R
9Combine the representative ring alkyl).Be more preferably Virahol and diphenyl-carbinol.
Above-mentioned replacement or the unsubstituted alkyl that contains 1 to 10 carbon atom be, for example: methyl, ethyl, sec.-propyl etc.Yet, methyl preferably.
Above-mentioned replacement or the unsubstituted aralkyl that contains 7 to 20 carbon atoms be, for example: benzyl, hydrocinnamyl, α-styroyl, to methoxybenzyl etc.
Above-mentioned replacement or the unsubstituted aryl that contains 6 to 20 carbon atoms be, for example: phenyl, to hydroxyphenyl, rubigan, p-nitrophenyl, naphthyl etc.
Above-mentioned cycloalkyl is, for example: cyclohexyl, cyclopentyl etc.
The method of reducing carbonyl compound of the present invention can be carried out with the following method:
At first, the prepared in reaction reductive agent of the alkylol cpd of organo-aluminium compound by general formula (10) and general formula (11).
The consumption of the organo-aluminium compound of above-mentioned general formula (10) is preferably 1 to 5 molar equivalent below 3 molar equivalents, be more preferably 1.5 to 3 molar equivalents, in the carbonyl compound of general formula (1).
The consumption of the alcohol of above-mentioned general formula (11) is below 3 molar equivalents, and 1 to 2 molar equivalent preferably is in the organo-aluminium compound of general formula (10).
The process of the alkylol cpd prepared in reaction reductive agent of the organo-aluminium compound of above-mentioned general formula (10) and above-mentioned general formula (11) can followingly be carried out: for example, the alkylol cpd of general formula (11) is added in the solution of toluene, tetrahydrofuran (THF), hexane or similar substance of organo-aluminium compound of general formula (10), stir the mixture then.The condition that adds alkylol cpd is not harsh, but ℃ adds between 60 ℃ more fortunately-10, is more preferably between 0 ℃ to 40 ℃ to add.Agitation condition is not harsh, stirs 1 to 10 hour but be preferably in 0 to 30 ℃.Also the organo-aluminium compound of general formula (10) can be added in the alkylol cpd of general formula (11).
Then, the carbonyl compound of general formula (1) is added reaction system, perhaps reductive agent is added in the carbonyl compound of general formula (1), stir the mixture with the carbonyl compound of realizing general formula (1) reduction.Reduction temperature is more fortunately-10 to 60 ℃ scope, better in-10 to 30 ℃ scope.
According to the present invention, carbonyl compound reduces with alkyl aluminium alcoholates (alkylaluminum alkoxide), and this alkyl aluminium alcoholates is different from the alkyl aluminium alcoholates that generates from the reactant carbonyl compound.In this case, suitably select the alkoxide groups of abovementioned alkyl aluminium alcoholates according to what generate as the alkoxide groups of intermediate from carbonyl compound, just might accelerate the formation speed of intermediate, the configuration that reacts at low temperatures and control reduzate alcohol.May be under the condition of gentleness the carbonyl compound of reduction-type (1), (6) or (7), and possible Stereoselective reduces some carbonyl compound, as α-ketone ester derivative, they almost can not be reduced by common tri-alkoxy aluminium.
For example, by the α-An Jichun derivative of the general formula (8) suitably selecting above-mentioned amido protecting group, just may make to have very high stereoselective erythro or the alpha-amino group halohydrin derivative of general formula (9).Thus, for example reduce optically active (S)-(1-benzyl-3-chloro-2-oxopropyl) t-butyl carbamate (it is the derivative of phenylalanine), can obtain the amino halohydrin of corresponding optical activity, its diastereomeric excess (d.e.) is not less than 94%.For example, use diphenyl-carbinol as alkylol cpd, can obtain the amino halohydrin of corresponding optical activity, its diastereomeric excess is shockingly high to 98%.Equally, in the example of reduction (S)-(t-butoxycarbonyl amino)-2-oxo-4-phenylbutyric acid methyl esters, can obtain corresponding optical activity alpha-hydroxy esters, it has very high erythro selectivity.Alpha-amino group ketone derivatives as the general formula (7) of raw material generally can prepare (as the flat 07-273547 of Japanese patent application) by corresponding alpha-amino acid derivatives (as α-An Jisuanzhi) and α-chloroacetic enolization magnesium (magnesiumenolate of α-chloroacetic acid) reaction.Obtain hiv protease inhibitor (a day disclosure is announced flat 08-99959) easily from the amino halohydrin of above-mentioned optical activity.
Following examples are to further specify of the present invention, but do not limit the scope of the invention.
Embodiment 1Preparation [1 (S)-benzyl-2 (S)-hydroxyl-3-chloropropyl] t-butyl carbamate (I)
With the 2-propyl alcohol of 0.76ml (10mmol) add 1.0M with the hexane solution of ice-cooled triisobutyl aluminium (10.5ml, 10.5mmol) in, mixture at room temperature stirred 30 minutes.With 10ml dilution with toluene mixture, add [1 (S)-benzyl-2-oxo-3-chloropropyl] t-butyl carbamate of 0.759g (2.5mmol) then, the mixture of gained at room temperature stirred 2 hours.Use the 1N hydrochloric acid hydrolysis, use ethyl acetate extraction, obtain the light yellow crystal of 0.840g after concentrating.The crystal of gained carries out quantitative analysis by HPLC, records productive rate and selection rate.
Productive rate: [1 (S)-benzyl-2 (S)-hydroxyl-3-chloropropyl] t-butyl carbamate 97.4%; [1 (S)-benzyl-2 (R)-hydroxyl-3-chloropropyl] t-butyl carbamate 2.6%.Selection rate: (1S, 2S) type/(1S, 2R) type=97.4/2.6.
Embodiment 2Preparation [1 (S)-benzyl-2 (S)-hydroxyl-3-chloropropyl] t-butyl carbamate (I)
With the three isopropoxy boranes of 0.47g (2.5mmol) add the 1.0M triisobutyl aluminium hexane solution (10.5ml, 10.5mmol) in, mixture is 170 ℃ of heating 2 hours down.After being cooled to 80 ℃, be decompressed to 10mmHg so that excessive triisobutyl borane distillation is removed.After being cooled to room temperature, use the 20ml dilution with toluene, add [1 (S)-benzyl-2-oxo-3-chloropropyl] t-butyl carbamate of 0.744g (2.5mmol) then, the mixture of gained at room temperature stirred 3 hours.Use the 1N hydrochloric acid hydrolysis, use ethyl acetate extraction, concentrate and obtain the 0.995g light yellow crystal.The crystal of gained carries out quantitative analysis by HPLC, records productive rate and selection rate.
Productive rate: [1 (S)-benzyl-2 (S)-hydroxyl-3-chloropropyl] t-butyl carbamate 80.1%; [1 (S)-benzyl-2 (R)-hydroxyl-3-chloropropyl] t-butyl carbamate 3.4%.Selection rate: (1S, 2S) type/(1S, 2R) type=95.9/4.1.
Embodiment 3Preparation [1 (S)-benzyl-2 (S)-hydroxyl-3-chloropropyl] t-butyl carbamate (I)
(about 1M, 10.4ml 10.4mmol), add 1.489g (5mmol) [1 (S)-benzyl-2-oxo-3-chloropropyl] t-butyl carbamate then, and mixture at room temperature stirred 24 hours with the hexane solution of 18ml dilution with toluene diethylaluminum ethoxide.After the quenching of 1N hydrochloric acid, the mixture ethyl acetate extraction.Concentrated extract obtains the 2.560g light yellow crystal.The crystal of gained carries out quantitative analysis by HPLC, records productive rate and selection rate.
Productive rate: [1 (S)-benzyl-2 (S)-hydroxyl-3-chloropropyl] t-butyl carbamate 55.7%; [1 (S)-benzyl-2 (R)-hydroxyl-3-chloropropyl] t-butyl carbamate 8.3%.Selection rate: (1S, 2S) type/(1S, 2R) type=87/13.
Embodiment 4Preparation [1 (S)-benzyl-2 (S)-hydroxyl-3-chloropropyl] t-butyl carbamate (I)
At room temperature (581mg, 10mmol) in the toluene solution (1.02M) of the DIBAH of adding 9.9ml (10mmol), mixture at room temperature stirred 1 hour with acetone.Then, add 1.489g (5mmol) [1 (S)-benzyl-2-oxo-3-chloropropyl] t-butyl carbamate, the gained mixture at room temperature stirred 2 hours.Behind the 1N hydrochloric acid hydrolysis, the reaction mixture ethyl acetate extraction.Concentrated extract obtains the 1.635g light yellow crystal.The crystal of gained carries out quantitative analysis by HPLC, records productive rate and selection rate.
Productive rate: [1 (S)-benzyl-2 (S)-hydroxyl-3-chloropropyl] t-butyl carbamate 82.6%; [1 (S)-benzyl-2 (R)-hydroxyl-3-chloropropyl] t-butyl carbamate 4.1%.Selection rate: (1S, 2S) type/(1S, 2R) type=95.2/4.8.
Embodiment 5Preparation [1 (S)-benzyl-2 (S)-hydroxyl-3-chloropropyl] t-butyl carbamate (I)
At room temperature (1.53ml, 20mmol) in the toluene solution (1.02M) of the DIBAH of adding 9.8ml (10mmol), mixture at room temperature stirred 1 hour with the 2-propyl alcohol.1.489g (5.0mmol) [1 (S)-benzyl-2-oxo-3-chloropropyl] t-butyl carbamate is added wherein, the gained mixture at room temperature stirred 2 hours again, then at the ice-cooled 1N hydrochloric acid hydrolysis of using down.Use ethyl acetate extraction, concentrate and obtain the 1.61g light yellow crystal.Purify with silica gel column chromatography (hexane/ethyl acetate) and to obtain 1.386g[1 (S)-benzyl-2 (S)-hydroxyl-3-chloropropyl] t-butyl carbamate (productive rate: 92.5%) and 33mg[1 (S)-benzyl-2 (R)-hydroxyl-3-chloropropyl] t-butyl carbamate (productive rate: 2.2%).(1S, 2S) type/(1S, 2R) type=97.7/2.3.
The NMR spectrogram of the product that obtains thus [1 (S)-benzyl-2 (S)-hydroxyl-3-chloropropyl] t-butyl carbamate as shown in Figure 1, its IR spectrogram is as shown in Figure 2.
[α
D 25]＝-3.44(c＝1.05，MeOH)
Fusing point: 168.5 to 169.5 ℃.
Embodiment 6Preparation [1 (S)-benzyl-2 (S)-hydroxyl-3-chloropropyl] t-butyl carbamate (I)
At room temperature (3.68g 20mmol) in the toluene solution (1.02M) of the DIBAH of adding 9.9ml (10mmol), and then adds 20ml toluene with diphenyl-carbinol.After mixture at room temperature stirs 1 hour, add 1.489g (5mmol) [1 (S)-benzyl-2-oxo-3-chloropropyl] t-butyl carbamate, the gained mixture at room temperature stirred 2 hours.Behind the 1N hydrochloric acid hydrolysis, the reaction mixture ethyl acetate extraction, the organic layer that obtains carries out quantitative analysis by HPLC, records productive rate and selection rate.
Productive rate: [1 (S)-benzyl-2 (S)-hydroxyl-3-chloropropyl] t-butyl carbamate 99.1%; [1 (S)-benzyl-2 (R)-hydroxyl-3-chloropropyl] t-butyl carbamate 0.9%.Selection rate: (1S, 2S) type/(1S, 2R) type=99.1/0.9.
Embodiment 7Preparation [1 (S)-benzyl-2 (S)-hydroxyl-3-chloropropyl] t-butyl carbamate (I)
At room temperature (2.0g 20mmol) adds in the toluene solution (1.02M) of 9.8ml (10mmol) DIBAH with 10ml toluene, and mixture at room temperature stirred 1 hour with hexalin.1.489g (5.0mmol) [1 (S)-benzyl-2-oxo-3-chloropropyl] t-butyl carbamate is added wherein, the gained mixture at room temperature stirred 2 hours again, then at the ice-cooled 1N hydrochloric acid hydrolysis of using down.Use ethyl acetate extraction, concentrate and obtain the 1.53g light yellow crystal.The crystal of gained carries out quantitative analysis by HPLC, records productive rate and selection rate.
Productive rate: [1 (S)-benzyl-2 (S)-hydroxyl-3-chloropropyl] t-butyl carbamate 93.4%; [1 (S)-benzyl-2 (R)-hydroxyl-3-chloropropyl] t-butyl carbamate 2.9%.Selection rate: (1S, 2S) type/(1S, 2R) type=97.0/3.0.
Embodiment 8Preparation [1 (S)-benzyl-2 (S)-hydroxyl-3-chloropropyl] Urethylane (II)
Follow the method for embodiment 1 and carry out, replace [1 (S)-benzyl-2-oxo-3-chloropropyl] t-butyl carbamate, obtain the 1.314g light yellow crystal with 1.28g (5mmol) [1 (S)-benzyl-2-oxo-3-chloropropyl] Urethylane.Recrystallization from hexane/ethyl acetate/ethanol obtains 1.063g[1 (S)-benzyl-2 (S)-hydroxyl-3-chloropropyl] Urethylane (productive rate: 78.0%).Mother liquor is analyzed with HPLC, is found to exist 60.0mg[1 (S)-benzyl-2 (S)-hydroxyl-3-chloropropyl] Urethylane (productive rate: 4.5%) and 36.1mg[1 (S)-benzyl-2 (R)-hydroxyl-3-chloropropyl] Urethylane (productive rate: 2.8%).The selection rate of total reaction product: (1S, 2S) type/(1S, 2R) type=96.7/3.3.
The NMR spectrogram of the product that obtains thus [1 (S)-benzyl-2 (S)-hydroxyl-3-chloropropyl] Urethylane as shown in Figure 3, its IR spectrogram is as shown in Figure 4.
Embodiment 9Preparation [1 (R)-thiophenyl methyl-2 (S)-hydroxyl-3-chloropropyl] benzyl carbamate (III)
At room temperature (26.44g 440mmol) adds in the toluene solution (1.02M) of 216ml (220mmol) DIBAH, and mixture at room temperature stirred 1 hour with the 2-propyl alcohol.39.6g (108.9mmol) [1 (R)-thiophenyl methyl-2-oxo-3-chloropropyl] benzyl carbamate is added wherein, the gained mixture at room temperature stirred 3 hours again, then at the ice-cooled 1N hydrochloric acid hydrolysis of using 500ml down.Behind the 300ml ethyl acetate extraction, extract washs with the sodium bicarbonate aqueous solution of 500ml 2% and the sodium chloride aqueous solution of 200ml 2% successively, uses anhydrous magnesium sulfate drying, concentrates and obtains the 75.6g faint yellow solid.The toluene/hexane crystallization of the solid of gained obtains 32.9g[1 (R)-thiophenyl methyl-2 (S)-hydroxyl-3-chloropropyl] benzyl carbamate (productive rate: 82.7%).Mother liquor is analyzed with HPLC, is found to exist 2.03g[1 (R)-thiophenyl methyl-2 (S)-hydroxyl-3-chloropropyl] benzyl carbamate (productive rate: 5.1%) and 1.753g[1 (R)-thiophenyl methyl-2 (R)-hydroxyl-3-chloropropyl] benzyl carbamate (productive rate: 4.4%).The selection rate of total reaction product: (1R, 2S) type/(1R, 2R) type=95.2/4.8.The NMR spectrogram of the product that obtains thus [1 (R)-thiophenyl methyl-2 (R)-hydroxyl-3-chloropropyl] benzyl carbamate as shown in Figure 5, its IR spectrogram is as shown in Figure 6.
Embodiment 10Preparation benzylalcohol
At room temperature (1.53ml 20mmol) adds in the toluene solution (1.02M) of 9.8ml (10mmol) DIBAH, and mixture at room temperature stirred 1 hour with the 2-propyl alcohol.The 0.531g phenyl aldehyde is added wherein, the gained mixture at room temperature stirred 2 hours again, then at the ice-cooled 1N hydrochloric acid hydrolysis of using down.Use ethyl acetate extraction, concentrate the benzylalcohol that obtains 615mg oily matter form.Analyze the oily matter that obtains with HPLC, find that transformation efficiency is 99.9%, productive rate is 78.0%.
Embodiment 11Preparation 1-phenyl-ethylene chlorhydrin
Follow the method for embodiment 10, replace phenyl aldehyde, obtain the 1-phenyl-ethylene chlorhydrin of the oily matter form of 809mg with 0.773g (5mmol) phenacyl chloride.Transformation efficiency: 97.5%; Productive rate: 80.4%.
Embodiment 12The preparation methyl phenyl carbinol
At room temperature (1.53ml 20mmol) adds in the toluene solution (1.02M) of 9.9ml (10mmol) DIBAH, and mixture at room temperature stirred 1 hour with the 2-propyl alcohol.Methyl phenyl ketone with 0.601g adds wherein again, and the gained mixture at room temperature stirred 6 hours, then at the ice-cooled 1N hydrochloric acid hydrolysis of using down.Use ethyl acetate extraction, concentrate the methyl phenyl carbinol that obtains 1.001g oily matter form.Transformation efficiency is 55%, and productive rate is 47.7%.
Embodiment 13The preparation methyl phenyl carbinol
At room temperature (3.68g 20mmol) adds in the toluene solution (1.02M) of 9.9ml (10mmol) DIBAH, and mixture at room temperature stirred 1 hour with diphenyl-carbinol.Methyl phenyl ketone with 0.601g (5mmol) adds wherein again, and the gained mixture at room temperature stirred 2 hours, then at the ice-cooled 1N hydrochloric acid hydrolysis of using down.Use ethyl acetate extraction, concentrate and obtain oily matter, carry out quantitative analysis with HPLC.Confirm thus to form methyl phenyl carbinol, productive rate is 42.3% (transformation efficiency is 53.3%).
Embodiment 14Preparation 2 (S)-hydroxyls-3 (S)-(t-butoxycarbonyl amino)-4-phenylbutyric acid methyl esters (IV)
At room temperature (0.737g 4mmol) adds in the toluene solution (1.02M) of 2ml (2.04mmol) DIBAH, and mixture at room temperature stirred 1 hour with diphenyl-carbinol.3 (S)-(t-butoxycarbonyl amino)-2-oxo-4-phenylbutyric acid methyl esters with 0.307g (1mmol) adds wherein again, and the gained mixture at room temperature stirred 2 hours, then at the ice-cooled 1N hydrochloric acid hydrolysis of using down.Use ethyl acetate extraction, concentrate extract, the oily matter of gained is purified with preparative thin layer chromatography, obtains the mixture of 217mg 2 (S)-hydroxyl-3 (S)-(t-butoxycarbonyl amino)-4-phenylbutyric acid methyl esters and 2 (R)-hydroxyls-3 (S)-(t-butoxycarbonyl amino)-4-phenylbutyric acid methyl esters.By the analysis of HPLC, find the diastereomer selection rate be (2S, 3S)/(2R, 3S)=94/6.
Productive rate: 2 (S)-hydroxyls-3 (S)-(t-butoxycarbonyl amino)-4-phenylbutyric acid methyl esters 65.9%; 2 (R)-hydroxyls-3 (S)-(t-butoxycarbonyl amino)-4-phenylbutyric acid methyl esters 4.2%.
The product 2 that obtains thus (R, S)-the NMR spectrogram of hydroxyl-3 (S)-(t-butoxycarbonyl amino)-4-phenylbutyric acid methyl esters as shown in Figure 7, its IR spectrogram is as shown in Figure 8.
Embodiment 15Preparation [1 (S)-benzyl-3,3-two chloro-2 (S)-hydroxypropyls] urethanum (V)
At room temperature (920mg 1.5mmol) adds in the toluene solution (1.01M) of 0.73ml (0.74mmol) DIBAH, and mixture at room temperature stirred 1 hour with the 2-propyl alcohol.Again with [1 (S)-benzyl-3 of 100mg (0.33mmol), 3-two chloro-2-oxopropyls] urethanum adds wherein, and the gained mixture at room temperature stirred 3.5 hours, stirred 2 hours down at 40 ℃ then, under room temperature, stirred 15 hours again, then at the ice-cooled 1N hydrochloric acid hydrolysis of using down.Use ethyl acetate extraction, concentrated extract obtains oily matter, purify with preparative thin layer chromatography, obtain [1 (S)-benzyl-3 of 66.7mg (0.22mmol), 3-two chloro-2 (S)-hydroxypropyls] mixture of urethanum and [1 (S)-benzyl-3,3-two chloro-2 (R)-hydroxypropyls] urethanum.The diastereomer selection rate that records by HPLC for (1S, 2S)/(1S, 2R)=95/5.
Productive rate: [1 (S)-benzyl-2 (S)-hydroxyl-3,3-two chloropropyls] urethanum 62.7%; [1 (S)-benzyl-2 (R)-hydroxyl-3,3-two chloropropyls] urethanum 33%.
The product that obtains thus [1 (S)-benzyl-3,3-two chloro-2 (R, S)-hydroxypropyl] urethanum the NMR spectrogram as shown in Figure 9, its IR spectrogram is as shown in figure 10.
Comparing embodiment 1Preparation [1 (S)-benzyl-2 (S), 3-epoxypropyl] t-butyl carbamate
A part of 0.976g of product [1 (S)-benzyl-2 (S)-hydroxyl-3-chloropropyl] t-butyl carbamate that obtains with embodiment 1 is suspended in the acetone of 8ml, adds the sodium hydroxide of 2ml 10% then, and mixture at room temperature stirred 1 hour.Separate water layer, concentrate organic layer, obtain [1 (S)-benzyl-2 (S), 3-epoxypropyl] t-butyl carbamate to doing.After the preparative thin layer chromatography purification, confirm that with chiral column (chiralcolumn) optical purity (optical purity) is 99.8%ee.
Comparing embodiment 2The preparation methyl phenyl carbinol
Methyl phenyl ketone (0.601g) is dissolved in the 15ml 2-propyl alcohol, adds the 2.04g aluminium isopropoxide, and the gained mixture stirred 4 hours down at 25 ℃.Behind the 1N hydrochloric acid hydrolysis, the mixture ethyl acetate extraction.Concentrate and obtain 0.564g oily matter, analyze with HPLC, transformation efficiency is 0.6%, and productive rate is 0.4%.
Comparing embodiment 3With Al (O-iPr)
3Reduction 3 (S)-(t-butoxycarbonyl amino)-2-oxo-4-phenylbutyric acid methyl esters
3 (S)-(t-butoxycarbonyl amino)-2-oxo-4-phenylbutyric acid methyl esters (307mg) is dissolved in the 6ml 2-propyl alcohol, adds the Al (O-iPr) of 204mg (2mmol)
3, mixture at room temperature stirred 1 hour, then 50 ℃ of following restir 15 hours.Yet, almost find to form reduzate 2 (R, S)-hydroxyl-3 (S)-(t-butoxycarbonyl amino)-4-phenylbutyric acid methyl esters.
Industrial usability
The present invention is by consisting of as mentioned above, and it is so that at a lower temperature simply and easily with the carbonyl compound object height Stereoselective is reduced to corresponding hydroxyl mixture becomes possibility. Therefore, the invention enables, for example exist Under the gentle condition from the derivative of amino halogenated ketone (from phenylalanine etc.) with high Stereoselective The derivative (it is the intermediate of the useful medicinal compound of preparation) for preparing amino halohydrin becomes possibility.
Claims (23)
1. the method for a reducing carbonyl compound comprises the organo-aluminium compound reaction with the carbonyl compound and the general formula (4) of general formula (1), obtains the alkylol cpd of corresponding general formula (5),
Wherein, in the general formula (1), if R
1And R
2In one be to replace or unsubstituted alkyl, replacement or unsubstituted aralkyl or replacement or the unsubstituted aryl that contains 6 to 30 carbon atoms, the then R that contains 7 to 30 carbon atoms that contains 1 to 30 carbon atom
1And R
2Expression replaces or unsubstituted alkyl, replacement or unsubstituted aralkyl, replacement or unsubstituted aryl, cyano group, hydrogen atom, the group of general formula (2) or the group of general formula (3) that contains 6 to 30 carbon atoms that contains 7 to 30 carbon atoms that contains 1 to 30 carbon atom separately;
CH
nX
3-n (2)
In the general formula (2), X represents halogen atom, and n represents 0 to 2 integer;
In the general formula (3), Y represents alkoxyl group, aralkoxy, replacement or unsubstituted amino or alkylthio;
In the general formula (4), R
3And R
4Expression replaces or unsubstituted alkyl, replacement or unsubstituted aralkyl or replacement or the unsubstituted aryl that contains 6 to 20 carbon atoms that contains 7 to 20 carbon atoms that contains 1 to 10 carbon atom R separately
5Expression replaces or unsubstituted primary alkyl, replacement or unsubstituted secondary alkyl, replacement or unsubstituted uncle's aralkyl or replacement or the unsubstituted secondary aralkyl that contains 7 to 30 carbon atoms that contains 7 to 30 carbon atoms that contains 1 to 20 carbon atom that contains 1 to 20 carbon atom;
In the general formula (5), R
1And R
2As above definition.
2. the method for reducing carbonyl compound as claimed in claim 1, the organo-aluminium compound that it is characterized in that general formula (4) is diisobutyl aluminum isopropoxide or diisobutyl hexichol aluminum methoxide.
3. the method for a reducing carbonyl compound comprises the carbonyl compound of general formula (1) with in advance obtaining the alkylol cpd of corresponding general formula (5) by the compound reaction of the alkylol cpd preparation of the organo-aluminium compound of general formula (10) and general formula (11),
R
5-OH (11)
Wherein, in the general formula (1), if R
1And R
2In one be to replace or unsubstituted alkyl, replacement or unsubstituted aralkyl or replacement or the unsubstituted aryl that contains 6 to 30 carbon atoms, the then R that contains 7 to 30 carbon atoms that contains 1 to 30 carbon atom
1And R
2Expression replaces or unsubstituted alkyl, replacement or unsubstituted aralkyl, replacement or unsubstituted aryl, cyano group, hydrogen atom, the group of general formula (2) or the group of general formula (3) that contains 6 to 30 carbon atoms that contains 7 to 30 carbon atoms that contains 1 to 30 carbon atom separately;
CH
nX
3-n (2)
In the general formula (2), X represents halogen atom, and n represents 0 to 2 integer;
In the general formula (3), Y represents alkoxyl group, aralkoxy, replacement or unsubstituted amino or alkylthio;
In the general formula (10), R
3And R
4Expression replaces or unsubstituted alkyl, replacement or unsubstituted aralkyl or replacement or the unsubstituted aryl that contains 6 to 20 carbon atoms that contains 7 to 20 carbon atoms that contains 1 to 10 carbon atom separately;
In the general formula (11), R
5Expression replaces or unsubstituted primary alkyl, replacement or unsubstituted secondary alkyl, replacement or unsubstituted uncle's aralkyl or replacement or the unsubstituted secondary aralkyl that contains 7 to 30 carbon atoms that contains 7 to 30 carbon atoms that contains 1 to 20 carbon atom that contains 1 to 20 carbon atom;
In the general formula (5), R
1And R
2As above definition.
4. the method for reducing carbonyl compound as claimed in claim 3 is characterized in that the organo-aluminium compound of general formula (10) is a diisobutyl aluminium hydride.
5. as the method for claim 3 or 4 described reducing carbonyl compounds, the alkylol cpd that it is characterized in that general formula (11) is the alkylol cpd of general formula (12),
Wherein, R
8And R
9Expression replaces or unsubstituted alkyl, replacement or unsubstituted aralkyl or replacement or the unsubstituted aryl that contains 6 to 20 carbon atoms, the perhaps R that contains 7 to 20 carbon atoms that contains 1 to 10 carbon atom separately
8With R
9Combine the representative ring alkyl.
6. the method for reducing carbonyl compound as claimed in claim 5 is characterized in that the alkylol cpd of general formula (12) is a Virahol.
7. the method for reducing carbonyl compound as claimed in claim 5 is characterized in that the alkylol cpd of general formula (12) is a diphenyl-carbinol.
8. as the method for claim 1,2,3,4,5,6 or 7 described reducing carbonyl compounds, it is characterized in that reduction reaction carries out under-10 ℃ to 30 ℃ temperature.
9. as the method for claim 1,2,3,4,5,6,7 or 8 described reducing carbonyl compounds, it is characterized in that:
In the carbonyl compound of general formula (1), R
1Be to replace or unsubstituted alkyl, replacement or unsubstituted aralkyl or replacement or the unsubstituted aryl that contains 6 to 30 carbon atoms that contains 7 to 30 carbon atoms that contains 1 to 30 carbon atom; R
2Be the group of general formula (2) or the group of general formula (3);
CH
nX
3-n (2)
Wherein, in the general formula (2), X represents halogen atom, and n represents 0 to 2 integer;
In the general formula (3), Y represents alkoxyl group, aralkoxy, replacement or unsubstituted amino or alkylthio.
10. a method for preparing the α-An Jichun derivative comprises the organo-aluminium compound reaction with the alpha-amino group ketone derivatives and the general formula (4) of general formula (6), obtains the compound of corresponding general formula (8),
Wherein, in the general formula (6), R
6Expression replaces or unsubstituted alkyl, replacement or unsubstituted aralkyl, replacement or unsubstituted aryl or the hydrogen atom that contains 6 to 20 carbon atoms that contains 7 to 20 carbon atoms that contains 1 to 20 carbon atom, R
7The group of expression general formula (2) or the group of general formula (3), P
1And P
2Represent hydrogen atom or amido protecting group, perhaps P separately
1With P
2Combine expression phthalyl group, but do not comprise P
1And P
2Be the situation of hydrogen atom;
CH
nX
3-n (2)
Wherein, in the general formula (2), X represents halogen atom, and n represents 0 to 2 integer;
In the general formula (3), Y represents alkoxyl group, aralkoxy, replacement or unsubstituted amino or alkylthio;
In the general formula (4), R
3And R
4Expression replaces or unsubstituted alkyl, replacement or unsubstituted aralkyl or replacement or the unsubstituted aryl that contains 6 to 20 carbon atoms that contains 7 to 20 carbon atoms that contains 1 to 10 carbon atom R separately
5Expression replaces or unsubstituted primary alkyl, replacement or unsubstituted secondary alkyl, replacement or unsubstituted uncle's aralkyl or replacement or the unsubstituted secondary aralkyl that contains 7 to 30 carbon atoms that contains 7 to 30 carbon atoms that contains 1 to 20 carbon atom that contains 1 to 20 carbon atom;
In the general formula (8), R
6, R
7, P
1And P
2As above definition.
11. the method for preparing the α-An Jichun derivative as claimed in claim 10, the organo-aluminium compound that it is characterized in that general formula (4) are diisobutyl aluminum isopropoxide or diisobutyl hexichol aluminum methoxide.
12. method for preparing the α-An Jichun derivative, comprise the alpha-amino group ketone derivatives of general formula (6) and compound reaction by the alkylol cpd prepared beforehand of the organo-aluminium compound of general formula (10) and general formula (11), obtain the compound of corresponding general formula (8)
R
5-OH (11)
Wherein, in the general formula (6), R
6Expression replaces or unsubstituted alkyl, replacement or unsubstituted aralkyl, replacement or unsubstituted aryl or the hydrogen atom that contains 6 to 20 carbon atoms that contains 7 to 20 carbon atoms that contains 1 to 20 carbon atom, R
7The group of expression general formula (2) or the group of general formula (3), P
1And P
2Represent hydrogen atom or amido protecting group, perhaps P separately
1With P
2Combine expression phthalyl group, but do not comprise P
1And P
2Be the situation of hydrogen atom;
CH
nX
3-n (2)
Wherein, in the general formula (2), X represents halogen atom, and n represents 0 to 2 integer;
In the general formula (3), Y represents alkoxyl group, aralkoxy, replacement or unsubstituted amino or alkylthio;
In the general formula (10), R
3And R
4Expression replaces or unsubstituted alkyl, replacement or unsubstituted aralkyl or replacement or the unsubstituted aryl that contains 6 to 20 carbon atoms that contains 7 to 20 carbon atoms that contains 1 to 10 carbon atom separately;
In the general formula (11), R
5Expression replaces or unsubstituted primary alkyl, replacement or unsubstituted secondary alkyl, replacement or unsubstituted uncle's aralkyl or replacement or the unsubstituted secondary aralkyl that contains 7 to 30 carbon atoms that contains 7 to 30 carbon atoms that contains 1 to 20 carbon atom that contains 1 to 20 carbon atom;
In the general formula (8), R
6, R
7, P
1And P
2As above definition.
13. the method for preparing the α-An Jichun derivative as claimed in claim 12 is characterized in that the organo-aluminium compound of general formula (10) is a diisobutyl aluminium hydride.
14. as claim 12 or the 13 described methods that prepare the α-An Jichun derivative, the alkylol cpd that it is characterized in that general formula (11) is the alkylol cpd of general formula (12),
Wherein, R
8And R
9Expression replaces or unsubstituted alkyl, replacement or unsubstituted aralkyl or replacement or the unsubstituted aryl that contains 6 to 20 carbon atoms, the perhaps R that contains 7 to 20 carbon atoms that contains 1 to 10 carbon atom separately
8With R
9Combine the representative ring alkyl.
15. the method for preparing the α-An Jichun derivative as claimed in claim 14 is characterized in that the alkylol cpd of general formula (12) is a Virahol.
16. the method for preparing the α-An Jichun derivative as claimed in claim 14 is characterized in that the alkylol cpd of general formula (12) is a diphenyl-carbinol.
17., it is characterized in that reduction reaction carries out under-10 ℃ to 30 ℃ temperature as claim 10,11,12,13,14, the 15 or 16 described methods that prepare the α-An Jichun derivative.
18., it is characterized in that in the alpha-amino group ketone derivatives of general formula (6) P as claim 10,11,12,13,14,15, the 16 or 17 described methods that prepare the α-An Jichun derivative
1And P
2In one be hydrogen atom, another is amino carbalkoxy or an aralkoxycarbonyl of protection.
19. as claim 10,11,12,13,14,15,16, the 17 or 18 described methods that prepare the α-An Jichun derivative, it is characterized in that the α-An Jichun derivative of the general formula (11) of gained is stereoselective, be erythro.
20. as claim 10,11,12,13,14,15,16,17, the 18 or 19 described methods that prepare the α-An Jichun derivative, the alpha-amino group ketone derivatives that it is characterized in that general formula (6) is the alpha-amino group halogenated derivative of general formula (7),
Wherein, X represents halogen atom, R
6Expression replaces or unsubstituted alkyl, replacement or unsubstituted aralkyl, replacement or unsubstituted aryl or the hydrogen atom that contains 6 to 20 carbon atoms that contains 7 to 20 carbon atoms that contains 1 to 20 carbon atom, P
1And P
2Represent hydrogen atom or amido protecting group, perhaps P separately
1With P
2Combine expression phthalyl group, but do not comprise P
1And P
2Be the situation of hydrogen atom;
The α-An Jichun derivative of general formula (8) is the alpha-amino group halohydrin derivative of general formula (9),
Wherein, X, R
6, P
1And P
2As above definition.
21. the method for preparing the α-An Jichun derivative as claimed in claim 20 is characterized in that the alpha-amino group halogenated derivative of general formula (7) is optically active
(S)-(1-benzyl-3-chloro-2-oxopropyl) t-butyl carbamate,
(R)-(1-benzyl-3-chloro-2-oxopropyl) t-butyl carbamate,
(S)-(1-benzyl-3-chloro-2-oxopropyl) Urethylane,
(R)-(1-benzyl-3-chloro-2-oxopropyl) Urethylane,
(S)-(1-benzyl-3-chloro-2-oxopropyl) urethanum,
(R)-(1-benzyl-3-chloro-2-oxopropyl) urethanum,
(S)-(1-benzyl-3-chloro-2-oxopropyl) benzyl carbamate,
(R)-(1-benzyl-3-chloro-2-oxopropyl) benzyl carbamate,
(S)-(1-thiophenyl methyl-3-chloro-2-oxopropyl) benzyl carbamate,
(R)-(1-thiophenyl methyl-3-chloro-2-oxopropyl) benzyl carbamate,
(S)-(1-thiophenyl methyl-3-chloro-2-oxopropyl) t-butyl carbamate,
(R)-(1-thiophenyl methyl-3-chloro-2-oxopropyl) t-butyl carbamate,
(S)-(1-thiophenyl methyl-3-chloro-2-oxopropyl) Urethylane,
(R)-(1-thiophenyl methyl-3-chloro-2-oxopropyl) Urethylane,
(S)-(1-thiophenyl methyl-3-chloro-2-oxopropyl) urethanum or
(R)-(1-thiophenyl methyl-3-chloro-2-oxopropyl) urethanum.
22. the method for preparing the α-An Jichun derivative as claimed in claim 20, the alpha-amino group halogenated derivative that it is characterized in that general formula (7) is (S)-(1-benzyl-3-chloro-2-oxopropyl) t-butyl carbamate or (S)-(1-thiophenyl methyl-3-chloro-2-oxopropyl) benzyl carbamate, the organo-aluminium compound of general formula (4) is a diisobutyl aluminium hydride, and the alkylol cpd of general formula (5) is Virahol or diphenyl-carbinol.
23. as claim 20, the 21 or 22 described methods that prepare the α-An Jichun derivative, it is characterized in that the alpha-amino group halohydrin derivative of the general formula (9) of gained is stereoselective, be erythro.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 97190044 CN1178517A (en) | 1996-01-29 | 1997-01-29 | Process for reduction of carbonyl compounds |
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| JP35632/96 | 1996-01-29 | ||
| JP37256/96 | 1996-01-30 | ||
| JP110317/96 | 1996-04-04 | ||
| CN 97190044 CN1178517A (en) | 1996-01-29 | 1997-01-29 | Process for reduction of carbonyl compounds |
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| CN 97190044 Pending CN1178517A (en) | 1996-01-29 | 1997-01-29 | Process for reduction of carbonyl compounds |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102766074A (en) * | 2012-08-07 | 2012-11-07 | 江西东邦药业有限公司 | Preparation method of anti-AIDs drug intermediates |
| CN110878003A (en) * | 2019-09-11 | 2020-03-13 | 安徽圣诺贝化学科技有限公司 | Isofol and new method for coproducing isophorol and carvone |
-
1997
- 1997-01-29 CN CN 97190044 patent/CN1178517A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102766074A (en) * | 2012-08-07 | 2012-11-07 | 江西东邦药业有限公司 | Preparation method of anti-AIDs drug intermediates |
| CN102766074B (en) * | 2012-08-07 | 2014-05-07 | 江西东邦药业有限公司 | Preparation method of anti-AIDs drug intermediates |
| CN110878003A (en) * | 2019-09-11 | 2020-03-13 | 安徽圣诺贝化学科技有限公司 | Isofol and new method for coproducing isophorol and carvone |
| CN110878003B (en) * | 2019-09-11 | 2023-03-28 | 安徽圣诺贝化学科技有限公司 | Isofol and new method for coproducing isophorol and carvone |
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